5-lipoxygenase-activating protein (flap) inhibitors

ABSTRACT

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of 5-lipoxygenase-activating protein (FLAP). Also described herein are methods of using such FLAP modulators, alone and in combination with other compounds, for treating respiratory, cardiovascular, and other leukotriene-dependent or leukotriene mediated conditions or diseases.

RELATED APPLICATIONS

This patent application claims the benefit of U.S. ProvisionalApplication Ser. No. 60/725,573, filed Oct. 11, 2005, hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds to treat or prevent diseases orconditions associated with 5-lipoxygenase-activating protein (FLAP)activity.

BACKGROUND OF THE INVENTION

The protein 5-lipoxygenase-activating protein (FLAP) is associated withthe pathway of leukotriene synthesis. In particular,5-lipoxygenase-activating protein (FLAP) is responsible for bindingarachidonic acid and transferring it to 5-lipoxygenase. See, e.g.,Abramovitz, M. et al., Eur. J. Biochem. 215:105-111 (1993).5-lipoxygenase can then catalyze the two-step oxygenation anddehydration of arachidonic acid, converting it into the intermediatecompound 5-HPETE (5-hydroperoxyeicosatetraenoic acid), and in thepresence of FLAP convert the 5-HPETE to Leukotriene A₄ (LTA₄).

Leukotrienes are biological compounds formed from arachidonic acid inthe leukotriene synthesis pathway (Samuelsson et al, Science, 220,568-575, 1983; Cooper, The Cell, A Molecular Approach, 2nd Ed. SinauerAssociates, Inc., Sunderland (Mass.), 2000). They are synthesizedprimarily by eosinophils, neutrophils, mast cells, basophils, dendriticcells, macrophages and monocytes. Leukotrienes have been implicated inbiological actions including, by way of example only, smooth musclecontraction, leukocyte activation, cytokine secretion, mucous secretion,and vascular function.

SUMMARY OF THE INVENTION

Presented herein are methods, compounds, pharmaceutical compositions,and medicaments for diagnosing, preventing, or treating diseases orconditions in which the activity of FLAP directly, or indirectly, causesat least one symptom of the disease or condition. Also presented hereinare methods, compounds, pharmaceutical compositions, and medicaments fordiagnosing, preventing, or treating leukotriene-dependent or leukotrienemediated diseases or conditions. Also presented herein are methods,compounds, pharmaceutical compositions, and medicaments for (a)diagnosing, preventing, or treating allergic and non-allergicinflammation, (b) controlling signs and symptoms that are associatedwith inflammation, and/or (c) controlling proliferative or metabolicdisorders. These disorders may arise from genetic, iatrogenic,immunological, infectious, metabolic, oncologic, toxic, and/or traumaticetiology. In one aspect, the methods, compounds, pharmaceuticalcompositions, and medicaments described herein comprise5-lipoxygenase-activating protein (FLAP) inhibitors described herein.

In one aspect are compounds of Formula (A), pharmaceutically acceptablesalts, pharmaceutically acceptable N-oxides, pharmaceutically activemetabolites, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable solvates thereof, which antagonize or inhibit FLAP and may beused to treat patients suffering from leukotriene-dependent orleukotriene mediated conditions or diseases, including, but not limitedto, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, arthritis,anaphylaxis, inflammatory bowel disease, adult respiratory distresssyndrome, myocardial infarction, aneurysm, stroke, cancer, endotoxicshock, proliferative disorders and inflammatory conditions;

wherein,

-   each A is independently selected from N or CR₅, and each A′ is    C-Z-Y, N or CR₅, provided that one A′ is C-Z-Y and the other A′ is N    or CR₅ and provided that the number of N groups from A plus the    number of N groups from A′ is 1 or 2;-   Z is selected from a bond, CR₁═CR₁, —C≡C—, C(R₂)_(n), C(R₁)₂O,    OC(R₁)₂, C(R₁)₂S(O)_(m), S(O)_(m)C(R₁)₂, C(R₁)₂NH, NHC(R₁)₂,    C(R₂)₂C(R₁)₂O, C(R₁)₂OC(R₁)₂, OC(R₁)₂C(R₂)₂, C(O)NH, NHC(O), wherein    each R₁ is independently H, CF₃, or an optionally substituted lower    alkyl; and each R₂ is independently H, OH, OMe, CF₃, or an    optionally substituted lower alkyl; m is 0, 1 or 2; n is 0, 1, 2, or    3;-   Y is a -L₁-(substituted or unsubstituted heterocycle),    -L₁-(substituted or unsubstituted heteroaryl), -L₁-(substituted or    unsubstituted aryl) or -L₁-C(═NR₃)N(R₄)₂, -L₁-NR₄C(═NR₃)N(R₄)₂,    -L₁-NRC(═CR₃)N(R₄)₂;    -   where R₃ is independently selected from H, —S(═O)₂R₄,        —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   each R₄ is independently selected from H, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        cycloalkyl;    -   or two R₄ groups can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring; and    -   or R₃ and R₄ groups can together form a 5-, 6-, 7-, or        8-membered heterocyclic ring;    -   where L₁ is a bond, a substituted or unsubstituted alkyl, a        substituted or unsubstituted alkenyl, a substituted or        unsubstituted alkynyl, a substituted or unsubstituted        heteroalkyl;-   R₆ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted or    unsubstituted cycloalkyl), L₂-(substituted or unsubstituted    alkenyl), L₂-(substituted or unsubstituted cycloalkenyl),    L₂-(substituted or unsubstituted heterocycle), L₂-(substituted or    unsubstituted heteroaryl), or L₂-(substituted or unsubstituted    aryl), where L₂ is a bond, O, S, —S(═O), —S(═O)2, C(O),    -(substituted or unsubstituted Cl-C₆ alkyl), or -(substituted or    unsubstituted C₂-C₆ alkenyl);-   R₇ is L₃-X-L₄-G, wherein,-   X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),    —C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,    —NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—,    —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,    —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—;-   L₃ is a bond, substituted or unsubstituted alkyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    aryl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocycle;-   L₄ is a bond, optionally substituted or unsubstituted alkyl,    optionally substituted or unsubstituted cycloalkyl, optionally    substituted or unsubstituted alkenyl, optionally substituted or    unsubstituted alkynyl;-   G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,    —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,    —C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,    —C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₉, -L₅-(substituted or    unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),    -L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted    or unsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH,    —C(O)O, or —OC(O);-   or G is W-G₁, where W is a substituted or unsubstituted aryl,    substituted or unsubstituted heterocycle or substituted or    unsubstituted heteroaryl and G₁ is H, —CO₂H, tetrazolyl,    —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,    —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₉)₂, —NR₉C(═NR₁₀)N(R₉)₂,    —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂, —CONHR₈, or —CON(R₈)₂;-   each R₈ is independently selected from substituted or unsubstituted    lower alkyl, substituted or unsubstituted lower cycloalkyl;-   each R₉ is independently selected from H, substituted or    unsubstituted lower alkyl, substituted or unsubstituted lower    cycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or    8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-,    6-, 7-, or 8-membered heterocyclic ring and-   each R₁₀ is independently selected from H, —S(═O)₂R₈,    —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;-   R₅ is H, halogen, —N₃, —CN, —ONO₂, -L₆-(substituted or unsubstituted    C₁-C₃ alkyl), -L₆-(substituted or unsubstituted C₂-C₄ alkenyl),    -L₆-(substituted or unsubstituted heteroaryl), or -L₆-(substituted    or unsubstituted aryl), wherein L₆ is a bond, O, S, —S(═O), S(═O)₂,    NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), —C(O)NH;-   R₁₁ is L₇-G, L₇-(substituted or unsubstituted cycloalkyl)-G,    L₇-(substituted or unsubstituted cycloalkenyl)-G, L₇-(substituted or    unsubstituted heteroaryl)-G, or L₇-(substituted or unsubstituted    aryl)-G, L₇-(substituted or unsubstituted-heterocycle)-G, where L₇    is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆    alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);-   R₁₂ is H, or L₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or    unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₄    alkenyl); L₉ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,    —OC(O)NH, —NHC(O)—, —C(O)NH—, —C(O)O—, or —OC(O)—; R₁₃, is H,    (substituted or unsubstituted C₁-C₆ alkyl), (substituted or    unsubstituted aryl), (substituted or unsubstituted heteroaryl), or    (substituted or unsubstituted heterocycle);-   or R₇ and R₁₂ can together form a 4 to 8-membered heterocyclic ring.

In a further or alternative embodiment, the “G” group of Formula (A) isany group that is used to tailor the physical and biological propertiesof the molecule. Such tailoring/modifications are achieved using groupswhich modulate acidity, basicity, lipophilicity, solubility and otherphysical properties of the molecule. The physical and biologicalproperties modulated by such modifications to G include, by way ofexample only, solubility, in vivo absorption, and in vivo metabolism. Inaddition, in vivo metabolism may include, by way of example only,controlling in vivo PK properties, off-target activities, potentialtoxicities associated with cypP450 interactions, drug-drug interactions,and the like. Further, modifications to G allow for the tailoring of thein vivo efficacy of the compound through the modulation of, by way ofexample, specific and non-specific protein binding to plasma proteinsand lipids and tissue distribution in vivo. Additionally, suchtailoring/modifications to G allow for the design of compounds selectivefor 5-lipoxygenase-activating protein over other proteins.

In further or alternative embodiments, G is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allow for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

In a further or alternative embodiment, the compound of Formula (A) hasthe following structure

while in a further or alternative embodiment, Z is —CH₂O—.

In a further or alternative embodiment, Y is -L₁-(substituted orunsubstituted aryl), -L₁-C(═NR₃)N(R₄)₂, -L₁-NR₄C(═NR₃)N(R₄)₂,-L₁-NR₄C(═CR₃)N(R₄)₂, or

wherein;

is a N-containing heterocycle selected from the group consisting of amonocyclic heterocycloalkyl, a monocyclic heteroaryl, a bicyclicheterocycloalkyl, a bicyclic heteroaryl, a multicyclic heterocycloalkyl,or a multicyclic heteroaryl; L₁ is a bond, a substituted orunsubstituted alkylene, substituted or unsubstituted alkenylene, orsubstituted or unsubstituted alkynylene, is a substituted orunsubstituted heteroalkylene, substituted or unsubstitutedheteroalkenylene, or substituted or unsubstituted heteroalkynylene; and

-   -   each R_(a) is independently H, halogen, —N₃, —CF₃, —CN, —NO₂,        OH, NH₂, -L_(a)-(substituted or unsubstituted alkyl),        -L_(a)-(substituted or unsubstituted alkenyl),        -L_(a)-(substituted or unsubstituted heteroaryl), or        -L_(a)-(substituted or unsubstituted aryl), wherein L_(a) is a        bond, O, S, —S(═O), —S(═O)₂, NH, C(O), CH₂, —NHC(O)O, —NHC(O),        or —C(O)NH, and n is 0, 1, 2, 3, 4, 5, or 6; or two R_(a) groups        on the same ring atom can together form an oxo.

In a further or alternative embodiment, the N is selected from the groupconsisting of quinolinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl,pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidonyl,piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl, benzothiazolyl,thiazolopyridinyl, oxazolyl, benzoxazolyl, oxazolopyridinyl,thiazolopyrimidinyl, oxazolopyrimidinyl, benzoxazinyl, andbenzothiazinyl.

In a further or alternative embodiment, the

is an N-containing monocyclic heteroaryl, while in further oralternative embodiments, the N-containing monocyclic heteroaryl isselected from the group consisting of pyridine, pyrazine, pyrimidine, orthiazole, each substituted or unsubstituted.

In a further Or alternative embodiment, the

is an N-containing a bicyclic heteroaryl, while in further oralternative emodiments the bicyclic heteroaryl is selected from thegroup consisting of quinoline or benzothiazole, each substituted orunsubstituted.

In a further or alternative embodiment, the

is an N-containing monocyclic heterocycloalkyl, while in further oralternative embodiments, the monocyclic heterocycloalkyl is selectedfrom the group consisting of pyrrolidone or piperidine, each substitutedor unsubstituted.

In a further or alternative embodiment, the

is an N-containing bicyclic heterocycloalkyl.

In a further or alternative embodiment, Y is -L₁-substituted orunsubstituted aryl, while in further or alternative embodiments, Y is-L₁-C(═NR₃)N(R₄)₂, -L₁-NR₄C(═NR₃)N(R₄)₂, -L₁-NR₄C(═CR₃)N(R₄)₂

In a further or alternative embodiment, R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted alkenyl),where L₂ is a bond, O, S, —S(═O), —S(O)₂, —C(O), or substituted orunsubstituted alkyl.

In a further or alternative embodiment, R₇ is (optionally substitutedalkylene)-X-L₄-G. In a further or alternative embodiment, G is H, —CO₂H,tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₈, —S(═O)₂R₈, or G is W-G₁, where W is a substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR_(10)N(R) ₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—CONH₂, —CONHR₈, or —CON(R₈)₂. In a further or alternative embodiment, Xis a bond, —O—, S, —S(O), —S(O)₂, —NR₈, —O—N═CH, —CH═N—O, —NHC(═O) or—C(═O)NH. In a further or alternative embodiment, R₁₁ is L₇-G,L₇-(substituted or unsubstituted heteroaryl)-G, L₇-(substituted orunsubstituted aryl)-G, or L₇-(substituted or unsubstitutedheterocycle)-G, where L₇ is a bond, —C(O), —C(O)NH, (substituted orunsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₆alkenyl). In a further or alternative embodiment, R₁₂ is H, orL₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₄ alkenyl); L₉ is a bond,—O—, —S—, —S(═O), —S(═O)₂, —NH—, —C(O)—, —(CH₂)—, —NHC(O)O—, —NHC(O)—,or —C(O)NH; R₁₃, is H or (substituted or unsubstituted C₁-C₆ alkyl).

In further or alternative embodiments, G is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allows for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

In further or alternative embodiments compounds of Formula (A) includecompounds having the structure of Formula (B), Formula (C), Formula (D),Formula (E), Formula (F), and Formula (G):

In further or alternative embodiments, Z is —CH₂O—, while in further oralternative embodiments, each R_(a) is independently selected from thegroup consisting of H, F, Cl, CF₃, OCH₃ and CH₃. In still further oralternative embodiments, R₆ is L₂-(substituted or unsubstituted alkyl),or L₂-(substituted or unsubstituted alkenyl), where L₂ is a bond, O, S,—S(═O), —S(O)₂, —C(O), or substituted or unsubstituted alkyl, while infurther or alternative embodiments, R₇ is (optionally substitutedalkylene)-X-L₈-G. In even further or alternative embodiments, G is H,—CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR_(C(═CR) ₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₈, —S(═O)₂R₈, or G is W-G₁, where W is a substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR_(C)(═CR,O)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂. In further or alternative embodiments, X is abond, —O—, —S, —S(O), —S(O)₂, —NR, —O—N═CH, —CH═N—O —NHC(═O) or—C(═O)NH, while in further or alternative embodiments, R₁₁ is L₇-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl). In even furtheror alternative embodiments, R₁₂ is H, or L₈-L₉-R₁₃, wherein L₈ is abond, (substituted or unsubstituted C₁-C₆ alkyl), or (substituted orunsubstituted C₂-C₄ alkenyl); L₉ is a bond, —O—, —S—, —S(═O), —S(═O)₂,—NH—, —C(O)—, —(CH₂)—, —NHC(O)O—, —NHC(O)—, or —C(O)NH; R₁₃, is H or(substituted or unsubstituted C₁-C₆ alkyl).

In further or alternative embodiments of such compounds of Formula (A),G is L₂₀-Q, wherein L₂₀ is an enzymatically cleavable linker and Q is adrug, or an affinity moiety. In further or alternative embodiments, thedrug includes, by way of example only, leukotriene receptor antagonistsand anti-inflammatory agents. In further or alternative embodiments, theleukotriene receptor antagonists include, but are not limited to,CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further oralternative embodiments, the affinity moiety allows for site specificbinding and include, but are not limited to, antibodies, antibodyfragments, DNA, RNA, siRNA, and ligands.

In further or alternative embodiments,

is selected from the group consisting of quinolinyl, isoquinolinyl,pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl,benzothiazolyl, thiazolopyridinyl, oxazolyl, benzoxazolyl,oxazolopyridinyl, thiazolopyrimidinyl, oxazolopyrimidinyl, benzoxazinyl,and benzothiazinyl.

In further or alternative embodiments, compounds of Formula (A) arecompounds having the structure of Formulas (I) to (XXIV):

Additionally, each of such embodiments further include embodiments inwhich the

moiety is selected from the group consisting of

In further or alternative embodiments, Z is —CH₂O—, while in further oralternative embodiments, R₆ is L₂-(substituted or unsubstituted alkyl),or L₂-(substituted or unsubstituted alkenyl), where L₂ is a bond, O, S,—S(═O), —S(O)₂, —C(O), or substituted or unsubstituted alkyl. In furtheror alternative embodiments, R₇ is is (optionally substitutedalkylene)-X-L₄-G, while in further or alternative embodiments, G is H,—CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₈, —S(═O)₂R₈, or G is W-G₁, where W is a substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG, is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR_(C(═CR) ₁₀)N(R₉)₂, —CO₂R₈,—CONH₂, —CONHR₈, or —CON(R₈)₂. In further or alternative embodiments, Xis a bond, —O—, —S, —S(O), —S(O)₂, —NR, —O—N═CH, —CH═N—O—NHC(═O) or—C(═O)NH, while in further or alternative embodiments, R₁₁ is L₇-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl). In further oralternative embodiments, R₁₂ is H, or L₈-L₉-R₁₃, wherein L₈ is a bond,(substituted or unsubstituted C₁-C₆ alkyl), or (substituted orunsubstituted C₂-C₄ alkenyl); L₉ is a bond, —O—, —S—, —S(═O), —S(═O)₂,—NH—, —C(O)—, —(CH₂)—, —NHC(O)O—, —NHC(O)—, or —C(O)NH; R₁₃, is H or(substituted or unsubstituted C₁-C₆ alkyl).

In further or alternative embodiments of such compounds of Formula (A),G is L₂₀-Q, wherein L₂₀ is an enzymatically cleavable linker and Q is adrug, or an affinity moiety. In further or alternative embodiments, thedrug includes, by way of example only, leukotriene receptor antagonistsand anti-inflammatory agents. In further or alternative embodiments, theleukotriene receptor antagonists include, but are not limited to,CysLT1/CysLT2 dual antagonists and CysLT1 antagonists. In further oralternative embodiments, the affinity moiety allows for site specificbinding and include, but are not limited to, antibodies, antibodyfragments, DNA, RNA, siRNA, and ligands.

In further or alternative embodiments, the compounds of Formula (A) maybe inhibitors of 5-lipoxygenase-activating protein (FLAP), while instill further or alternative embodiments, such inhibitors are selectivefor FLAP. In even further or alternative embodiments, such inhibitorshave an IC₅₀ below 50 microM in the FLAP binding assay.

In further or alternative embodiments, the compounds of Formula (A) maybe included into pharmaceutical compositions or medicaments used fortreating a leukotriene-dependent or leukotriene mediated condition ordisease in a patient.

In another aspect the inflammatory conditions include, but are notlimited to, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, aortic aneurysm,myocardial infarction, and stroke. In other aspects the proliferativedisorders include, but are not limited to, cancer and noncancerousdisorders, including, but not limited to, those involving the skin orlymphatic tissues. In other aspects the metabolic disorders include, butare not limited to, bone remodeling, loss or gain. In additionalaspects, such conditions are iatrogenic and increases in, or abnormallocalization of, leukotrienes may be induced by other therapies ormedical or surgical procedures.

In other aspects, the methods, compounds, pharmaceutical compositions,and medicaments described herein may be used to prevent the cellularactivation of 5-lipoxygenase, while in other aspects the methods,compounds, pharmaceutical compositions, and medicaments described hereinmay be used to limit the formation of leukotrienes. In other aspects,such methods, compounds, pharmaceutical compositions, and medicamentsmay comprise FLAP inhibitors disclosed herein for the treatment ofasthma by (a) lowering the concentrations of leukotrienes in certaintissue(s) of the body or in the entire body of a patient, (b) modulatingthe activity of enzymes or proteins in a patient wherein such enzymes orproteins are involved in the leukotriene pathway such as, by way ofexample, 5-lipoxygenase-activating protein or 5-lipoxygenase, or (c)combining the effects of (a) and (b). In yet other aspects, the methods,compounds, pharmaceutical compositions, and medicaments described hereinmay be used in combination with other medical treatments or surgicalmodalities.

In one aspect are methods for reducing/inhibiting the leukotrienesynthetic activity of 5-lipoxygenase-activating protein (FLAP) in amammal comprising administering to the mammal at least once an effectiveamount of a compound having the structure of Formula (A):

wherein,

-   each A is independently selected from N or CR₅, and each A′ is    C-Z-Y, N or CR₅, provided that one A′ is C-Z-Y and the other A′ is N    or CR₅ and provided that the number of N groups from A plus the    number of N groups from A′ is 1 or 2;-   Z is selected from a bond, CR₁═CR₁, —C≡C—, C(R₂)_(n), C(R₁l)₂O,    OC(R₁)₂, C(R₁)₂S(O)_(m), S(O)_(m)C(R₁)₂, C(R₁)₂NH, NHC(R₁)₂,    C(R₂)₂C(R¹)₂O, C(R₁)₂OC(R₁)₂, OC(R¹)₂C(R₂)₂, C(O)NH, NHC(O), wherein    each R₁ is independently H, CF₃, or an optionally substituted lower    alkyl; and each R₂ is independently H, OH, OMe, CF₃, or an    optionally substituted lower alkyl; m is 0, 1 or 2; n is 0, 1, 2, or    3;-   Y is a -L₁-(substituted or unsubstituted heterocycle),    -L₁-(substituted or unsubstituted heteroaryl), -L₁-(substituted or    unsubstituted aryl) or -L₁-C(═NR₃)N(R₄)₂, -L₁-NR₄C(═NR₃)N(R₄)₂,    -L₁-NR₄C(═CR₃)N(R₄)_(2;)    -   where R₃ is independently selected from H, —S(═O)₂R₄,        —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   each R₄ is independently selected from H, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        cycloalkyl;    -   or two R₄ groups can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring; and    -   or R₃ and R₄ groups can together form a 5-, 6-, 7-, or        8-membered heterocyclic ring;    -   where L₁ is a bond, a substituted or unsubstituted alkyl, a        substituted or unsubstituted alkenyl, a substituted or        unsubstituted alkynyl, a substituted or unsubstituted        heteroalkyl;-   R₆ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted or    unsubstituted cycloalkyl), L₂-(substituted or unsubstituted    alkenyl), L₂-(substituted or unsubstituted cycloalkenyl),    L₂-(substituted or unsubstituted heterocycle), L₂-(substituted or    unsubstituted heteroaryl), or L₂-(substituted or unsubstituted    aryl), where L₂ is a bond, O, S, —S(═O), —S(═O)₂, C(O),    -(substituted or unsubstituted C₁-C₆ alkyl), or -(substituted or    unsubstituted C₂-C₆ alkenyl);-   R₇ is L₃-X-L₄-G, wherein,-   X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),    —C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,    —NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—,    —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,    —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—;-   L₃ is a bond, substituted or unsubstituted alkyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    aryl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocycle;-   L₄ is a bond, optionally substituted or unsubstituted alkyl,    optionally substituted or unsubstituted cycloalkyl, optionally    substituted or unsubstituted alkenyl, optionally substituted or    unsubstituted alkynyl;-   G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,    —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,    —C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,    —C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or    unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),    -L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted    or unsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH,    —C(O)O, or —OC(O);-   or G is W-G₁, where W is a substituted or unsubstituted aryl,    substituted or unsubstituted heterocycle or substituted or    unsubstituted heteroaryl and G₁ is H, —CO₂H, tetrazolyl,    —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,    —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₉)₂ —NR₉C(═NR₁₀)N(R₉)₂,    —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂, —CONHR₈, or —CON(R₈)₂;-   each R₈ is independently selected from substituted or unsubstituted    lower alkyl, substituted or unsubstituted lower cycloalkyl;-   each R₉ is independently selected from H, substituted or    unsubstituted lower alkyl, substituted or unsubstituted lower    cycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or    8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-,    6-, 7-, or 8-membered heterocyclic ring and-   each R₁₀ is independently selected from H, —S(═O)₂R₈,    —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;-   R₅ is H, halogen, —N₃, —CN, —ONO₂, -L₆-(substituted or unsubstituted    C₁-C₃ alkyl), -L₆-(substituted or unsubstituted C₂-C₄ alkenyl),    -L₆-(substituted or unsubstituted heteroaryl), or -L₆-(substituted    or unsubstituted aryl), wherein L₆ is a bond, O, S, —S(═O), S(═O)₂,    NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), —C(O)NH;-   R₁₁ is L₇-G, L₇-(substituted or unsubstituted cycloalkyl)-G,    L₇-(substituted or unsubstituted cycloalkenyl)-G, L₇-(substituted or    unsubstituted heteroaryl)-G, or L₇-(substituted or unsubstituted    aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G, where L₇    is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆    alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);-   R₁₂ is H, or L₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or    unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₄    alkenyl); L is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,    —OC(O)NH, —NHC(O)—, —C(O)NH—, —C(O)O—, or —OC(O)—; R₁₃, is H,    (substituted or unsubstituted C₁-C₆ alkyl), (substituted or    unsubstituted aryl), (substituted or unsubstituted heteroaryl), or    (substituted or unsubstituted heterocycle);-   or R₇ and R₁₂ can together form a 4 to 8-membered heterocyclic ring,    or pharmaceutically acceptable salt, or a pharmaceutically    acceptable prodrug.

In a further or alternative embodiment, the “G” group of Formula (A) isany group that is used to tailor the physical and biological propertiesof the molecule. Such tailoring/modifications are achieved using groupswhich modulate acidity, basicity, lipophilicity, solubility and otherphysical properties of the molecule. The physical and biologicalproperties modulated by such modifications to G include, by way ofexample only, solubility, in vivo absorption, and in vivo metabolism. Inaddition, in vivo metabolism may include, by way of example only,controlling in vivo PK properties, off-target activities, potentialtoxicities associated with cypP450 interactions, drug-drug interactions,and the like. Further, modifications to G allow for the tailoring of thein vivo efficacy of the compound through the modulation of, by way ofexample, specific and non-specific protein binding to plasma proteinsand lipids and tissue distribution in vivo. Additionally, suchtailoring/modifications to G allow for the design of compounds selectivefor 5-lipoxygenase-activating protein over other proteins. In further oralternative embodiments, G is L₂₀-Q, wherein L₂₀ is an enzymaticallycleavable linker and Q is a drug, or an affinity moiety. In further oralternative embodiments, the drug includes, by way of example only,leukotriene receptor antagonists and anti-inflammatory agents. Infurther or alternative embodiments, the leukotriene receptor antagonistsinclude, but are not limited to, CysLT1/CysLT2 dual antagonists andCysLT1 antagonists. In further or alternative embodiments, the affinitymoiety allows for site specific binding and include, but are not limitedto, antibodies, antibody fragments, DNA, RNA, siRNA, and ligands.

In another aspect are methods for modulating, including reducing and/orinhibiting the activity of 5-lipoxygenase activating protein, directlyor indirectly, in a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (A).

In another aspect are methods for modulating, including reducing and/orinhibiting the activity of leukotrienes in a mammal, directly orindirectly, comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (A).

In another aspect are methods for treating leukotriene-dependent orleukotriene mediated conditions or diseases, comprising administering tothe mammal at least once an effective amount of at least one compoundhaving the structure of Formula (A).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A).

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (A). In afurther embodiment of this aspect, the respiratory disease is asthma. Ina further embodiment of this aspect, the respiratory disease includes,but is not limited to, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-inducedasthma, isocapnic hyperventilation, child-onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, seasonal asthma.

In another aspect are methods for treating chronic obstructive pulmonarydisease comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (A). In a further embodiment of this aspect, chronic obstructivepulmonary disease includes, but is not limited to, chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation and cystic fibrosis.

In another aspect are methods for preventing increased mucosal secretionand/or edema in a disease or condition comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (A).

In another aspect are methods for treating vasoconstriction,atherosclerosis and its sequelae myocardial ischemia, myocardialinfarction, arterial aneurysm, vasculitis and stroke comprisingadministering to the mammal an effective amount of a compound having thestructure of Formula (A).

In another aspect are methods for treating organ reperfusion injuryfollowing organ ischemia and/or endotoxic shock comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (A).

In another aspect are methods for reducing the constriction of bloodvessels in a mammal comprising administering to the mammal at least oncean effective amount of at least one compound having the structure ofFormula (A).

In another aspect are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (A).

In another aspect are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte recruitmentcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (A).

A further aspect are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (A

In another aspect are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering to the mammal at least once aneffective amount of at least one having the structure of Formula (A).

In another aspect are methods for treating CNS disorders comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A). CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, peripheralneuropathy/neuropathic pain, spinal cord injury, cerebral edema and headinjury.

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A). The type ofcancer may include, but is not limited to, pancreatic cancer and othersolid or hematological tumors.

In another aspect are methods for preventing endotoxic shock and septicshock comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (A).

In another aspect are methods for preventing rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (A).

In another aspect are methods for preventing increased GI diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (A). Suchdiseases include, by way of example only, chronic gastritis,eosinophilic gastroenteritis, and gastric motor dysfunction.

A further aspect are methods for treating kidney diseases comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A). Such diseasesinclude, by way of example only, glomerulonephritis, cyclosporinenephrotoxicity renal ischemia reperfusion.

In another aspect are methods for preventing or treating acute orchronic renal insufficiency comprising administering to the mammal atleast once an effective amount of at least one compound having thestructure of Formula (A).

In another aspect are methods for treating type II diabetes comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A).

In another aspect are methods to diminish the inflammatory aspects ofacute infections within one or more solid organs or tissues such as thekidney with acute pyelonephritis.

In another aspect are methods for preventing or treating acute orchronic disorders involving recruitment or activation of eosinophilscomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (A).

In another aspect are methods for preventing or treating acute orchronic erosive disease or motor dysfunction of the gastrointestinaltract caused by non-steroidal anti-inflammatory drugs (includingselective or non-selective cyclooxygenase-1 or -2 inhibitors) comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A).

A further aspect are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (A).Such inflammatory responses of the skin include, by way of example,dermatitis, contact dermatitis, eczema, urticaria, rosacea, andscarring. In another aspect are methods for reducing psoriatic lesionsin the skin, joints, or other tissues or organs, comprisingadministering to the mammal an effective amount of a first compoundhaving the structure of Formula (A).

A further aspect are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringto the mammal at least once an effective amount of at least one compoundhaving the structure of Formula (A).

A further aspect are methods for the treatment of metabolic syndromessuch as Familial Mediterranean Fever comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula(A).

In a further aspect are methods to treat hepatorenal syndrome comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (A).

In another aspect is the use of a compound of Formula (A) in themanufacture of a medicament for treating an inflammatory disease orcondition in an animal in which the activity of at least one leukotrieneprotein contributes to the pathology and/or symptoms of the disease orcondition. In one embodiment of this aspect, the leukotriene pathwayprotein is 5-lipoxygenase-activating protein (FLAP). In another orfurther embodiment of this aspect, the inflammatory disease orconditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) theeffective amount of the compound is systemically administered to themammal; and/or (b) the effective amount of the compound is administeredorally to the mammal; and/or (c) the effective amount of the compound isintravenously administered to the mammal; and/or (d) the effectiveamount of the compound administered by inhalation; and/or (e) theeffective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically (dermal) to the mammal; and/or(h) the effective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments in whichthe mammal is a human, including embodiments wherein (a) the human hasan asthmatic condition or one or more other condition(s) selected fromthe group consisting of allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, or seasonal asthma, or chronic obstructivepulmonary disease, or pulmonary hypertension or interstitial lungfibrosis. In any of the aforementioned aspects are further embodimentsin which the mammal is an animal model for pulmonary inflammation,examples of which are provided herein.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredin a single dose; (ii) the time between multiple administrations isevery 6 hours; (iii) the compound is administered to the mammal every 8hours;. In further or alternative embodiments, the method comprises adrug holiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. The length of the drug holiday can vary from 2 days to 1 year.

In any of the aforementioned aspects involving the treatment ofleukotriene dependent diseases or conditions are further embodimentscomprising administering at least one additional agent, each agent maybe administered in any order, including, by way of example, ananti-inflammatory agent, a different compound having the structure ofFormula (A), a CysLT₁ receptor antagonist, or a CysLT₁/CysLT₂ dualreceptor antagonist. In further or alternative embodiments, the CysLT₁antagonist is selected from montelukast (Singulair™:[1-[[1-[3-[2-[(7-chloro-2-quinolyl)]vinyl]phenyl]-3-[2-(1-hydroxy-1-methyl-ethyl)phenyl]-propyl]sulfanylmethyl]cyclopropyl]aceticacid), zafirlukast (Accolate™:3-[[2-methoxy4-(o-tolylsulfonylcarbamoyl)phenyl]methyl]-1-methyl-1H-indol-5-yl]aminoformicacid cyclopentyl ester) or pranlukast (Onon™:4-oxo-8-[p-(4-phenylbutyloxy)benzoylamino]-2-tetrazol-5-yl)-4H-1-benzopyran)

In further or alternative embodiments, the anti-inflammatory agentincludes, but is not limited to, non-steroidal anti-inflammatory drugssuch as a cyclooxygenase inhibitor (COX-1 and/or COX-2), lipoxygenaseinhibitors and steroids such as prednisone or dexamethasone. In furtheror alternative embodiments, the anti-inflammatory agent is selected fromthe group consisting of Arthrotec™, Asacol, Auralgan®, Azulfidine,Daypro, etodolac, Ponstan, Salofalk, Solu-Medrol, aspirin, indomethacin(Indocin™), rofecoxib (Vioxx™), celecoxib (Celebrex™), valdecoxib(Bextra™), diclofenac, etodolac, ketoprofen, Lodine, Mobic, nabumetone,naproxen, piroxicam, Celestone, prednisone, Deltasone, or any genericequivalent thereof.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent that may beselected from the group consisting of alemtuzumab, arsenic trioxide,asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-basedcompounds such as cisplatin, cladribine,daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine,5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™, taxol,temozolomide, thioguanine, or classes of drugs including hormones (anantiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In any of the aforementioned aspects involving the therapy oftransplanted organs or tissues or cells are further embodimentscomprising administering at least one additional agent selected from thegroup consisting of azathioprine, a corticosteroid, cyclophosphamide,cyclosporin, dacluzimab, mycophenolate mofetil, OKT3, rapamycin,tacrolimus, or thymoglobulin.

In any of the aforementioned aspects involving the therapy ofinterstitial cystitis are further embodiments comprising administeringat least one additional agent selected from dimethylsulfoxide,omalizumab, and pentosan polysulfate.

In any of the aforementioned aspects involving the therapy of disordersof bone are further embodiments comprising administering at least oneadditional agent selected from the group consisting of minerals,vitamins, bisphosphonates, anabolic steroids, parathyroid hormone oranalogs, and cathepsin K inhibitors dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of inflammation are further embodiments comprising: (a)monitoring inflammation in a mammal; (b) measuring bronchoconstrictionin a mammal; (c) measuring eosinophil and/or basophil and/or dendriticcell and/or neutrophil and/or monocyte and/or lymphocyte recruitment ina mammal; (d) monitoring mucosal secretion in a mammnal; (e) measuringmucosal edema in a mammal; (e) measuring levels of LTB₄ in the calciumionophore-challenged blood of a mammal; (f) measuring levels of LTE₄ inthe urinary excretion of a mammal; or (g) identifying a patient bymeasuring leukotriene-driven inflammatory biomarkers such as LTB₄, LTC₄,Il-6, CRP, SAA, MPO, EPO, MCP-1, MIP-α, sICAMs, Il-4, Il-13.

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients byscreening for a leukotriene gene SNP or haplotype. In further oralternative embodiments the leukotriene gene SNP or haplotype is aleukotriene pathway gene, while in still further or alternativeembodiments, the leukotriene gene SNP or haplotype is a5-lipoxygenase-activating protein (FLAP) SNP or haplotype.

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients bymonitoring the patient for either:

-   i) at least one leukotriene related inflammatory biomarker; or-   ii) at least one functional marker response to a leukotriene    modifying agent; or-   iii) at least one leukotriene related inflammatory biomarker and at    least one functional marker response to a leukotriene modifying    agent.    In further or alternative embodiments, the leukotriene-related    inflammatory biomarkers are selected from the group consisting of    LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-α,    sICAM, IL-6, IL-4, and IL-13, while in still further or alternative    embodiments, the functional marker response is significant lung    volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients byeither:

-   i) screening the patient for at least one leukotriene gene SNP    and/or haplotype including SNP's in intronic or exonic locations; or-   ii) monitoring the patient for at least one leukotriene driven    inflammatory biomarker; or-   ii) monitoring the patient for at least one functional marker    response to a leukotriene modifying agent    In further or alternative embodiments, the leukotriene gene SNP or    haplotype is a leukotriene pathway gene. In still further or    alternative embodiments, the leukotriene gene SNP or haplotype is a    5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In    further or alternative embodiments, the leukotriene-driven    inflammatory biomarkers are selected from the group consisting of    LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-α,    sICAM, IL-6, IL-4, and IL-13, while in still further or alternative    embodiments, the functional marker response is significant lung    volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients by atleast two of the following:

-   i) screening the patient for at least one leukotriene gene SNP or    haplotype;-   ii) monitoring the patient for at least one leukotriene driven    inflammatory biomarker;-   ii) monitoring the patient for at least one functional marker    response to a leukotriene modifying agent.    In further or alternative embodiments, the leukotriene gene SNP or    haplotype is a leukotriene pathway gene. In still further or    alternative embodiments, the leukotriene gene SNP or haplotype is a    5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In    further or alternative embodiments, the leukotriene-driven    inflammatory biomarkers are selected from the group consisting of    LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-α,    sICAM, IL-6, IL-4, and IL-13, while in still further or alternative    embodiments, the functional marker response is significant lung    volume (FEV1).

In any of the aforementioned aspects involving the prevention ortreatment of leukotriene-dependent or leukotriene mediated diseases orconditions are further embodiments comprising identifying patients by:

-   i) screening the patient for at least one leukotriene gene SNP or    haplotype; and-   ii) monitoring the patient for at least one leukotriene driven    inflammatory biomarker; and-   ii) monitoring the patient for at least one functional marker    response to a leukotriene modifying agent.    In further or alternative embodiments, the leukotriene gene SNP or    haplotype is a leukotriene pathway gene. In still further or    alternative embodiments, the leukotriene gene SNP or haplotype is a    5-lipoxygenase-activating protein (FLAP) SNP or haplotype. In    further or alternative embodiments, the leukotriene-driven    inflammatory biomarkers are selected from the group consisting of    LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO, EPO, MCP-1, MIP-α,    sICAM, IL-6, IL-4, and IL-13, while in still further or alternative    embodiments, the functional marker response is significant lung    volume (FEV1).

In another aspect is the prevention or treatment ofleukotriene-dependent or leukotriene mediated diseases or conditionscomprising administering to a patient an effective amount of a FLAPmodulator, wherein the patients has been identified using informationobtained by:

-   i) screening the patient for at least one leukotriene gene SNP or    haplotype; and-   ii) monitoring the patient for at least one leukotriene driven    inflammatory biomarker; and-   ii) monitoring the patient for at least one functional marker    response to a leukotriene modifying agent.    In further or alternative embodiments, the FLAP modulator is a FLAP    inhibitor. In further or alternative embodiments, the leukotriene    gene SNP or haplotype is a leukotriene pathway gene. In still    further or alternative embodiments, the leukotriene gene SNP or    haplotype is a 5-lipoxygenase-activating protein (FLAP) SNP or    haplotype. In further or alternative embodiments, the    leukotriene-driven inflammatory biomarkers are selected from the    group consisting of LTB₄, cysteinyl leukotrienes, CRP, SAA, MPO,    EPO, MCP-1, MIP-α, sICAM, IL-6, IL-4, and IL-13, while in still    further or alternative embodiments, the functional marker response    is significant lung volume (FEV1). In further or alternative    embodiments, the information obtained from the three diagnostic    methods may be used in an algorithm in which the information is    analyzed to identify patients in need of treatment with a FLAP    modulator, the treatment regimen, and the type of FLAP modulator    used.

In any of the aforementioned aspects the leukotriene-dependent orleukotriene mediated diseases or conditions include, but are not limitedto, asthma, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, rhinitis, arthritis, allergy,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, and endotoxic shock.

Certain Chemical Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A(2000) and B (2001), Plenum Press, New York. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylmoiety may be a “saturated alkyl” group, which means that it does notcontain any alkene or alkyne moieties. The alkyl moiety may also be an“unsaturated alkyl” moiety, which means that it contains at least onealkene or alkyne moiety. An “alkene” moiety refers to a group consistingof at least two carbon atoms and at least one carbon-carbon double bond,and an “alkyne” moiety refers to a group consisting of at least twocarbon atoms and at least one carbon-carbon triple bond. The alkylmoiety, whether saturated or unsaturated, may be branched, straightchain, or cyclic.

The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl

group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,etc., up to and including 10 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group could also be a “loweralkyl” having 1 to 5 carbon atoms. The alkyl group of the compoundsdescribed herein may be designated as “C₁-C₄ alkyl” or similardesignations. By way of example only, “C₁-C₄ alkyl” indicates that thereare one to four carbon atoms in the alkyl chain, i.e., the alkyl chainis selected from the group consisting of methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl,propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andthe like.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from the group x=1, y=1 and x=2, y=0. When x=2, thealkyl groups, taken together, can optionally form a cyclic ring system.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═C—R, wherein R refers to the remaining portions of the alkenylgroup, which may be the same or different. Non-limiting examples of analkenyl group include —CH═CH, —C(CH₃)═CH, —CH═CCH₃ and —C(CH₃)═CCH₃. Thealkenyl moiety may be branched, straight chain, or cyclic (in whichcase, it would also be known as a “cycloalkenyl” group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group, which may be the same or different.Non-limiting examples of an alkynyl group include —C≡CH, —C≡CH₃ and—C≡CCH₂CH₃. The “R” portion of the alkynyl moiety may be branched,straight chain, or cyclic.

An “amide” is a chemical moiety with formula —C(O)NHR or —NHC(O)R, whereR is selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). An amide may be an amino acid or a peptidemolecule attached to a compound of Formula (A), thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “aromatic” or “aryl” refers to an aromatic group which has atleast one ring having a conjugated pi electron system and includes bothcarbocyclic aryl (e.g., phenyl) and heterocyclic aryl (or “heteroaryl”or “heteroaromatic”) groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of carbon atoms) groups. The term “carbocyclic” refers to acompound which contains one or more covalently closed ring structures,and that the atoms forming the backbone of the ring are all carbonatoms. The term thus distinguishes carbocyclic from heterocyclic ringsin which the ring backbone contains at least one atom which is differentfrom carbon.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

A “cyano” group refers to a —CN group.

The term “cycloalkyl” refers to a monocyclic or polycyclic radical thatcontains only carbon and hydrogen, and may be saturated, partiallyunsaturated, or fully unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms. Illustrative examples of cycloalkylgroups include the following moieties:

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from the group consisting of alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and heteroalicyclic (bondedthrough a ring carbon). Any hydroxy, or carboxyl side chain on thecompounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety. The term “halo” or, alternatively, “halogen” means fluoro,chloro, bromo or iodo.

The term “fused-pyrrolo scaffold,” as used herein refers to the moietyhaving the following chemical structure

wherein the fused-pyrrolo scaffold includes, but is not limited to,pyrrolo-pyridines, pyrrolo-pyrimidines, pyrrolo-pyrazines, andpyrrolo-pyridazines.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures that aresubstituted with one or more halo groups or with combinations thereof.The terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl andhaloalkoxy groups, respectively, in which the halo is fluorine.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl radicals and whichhave one or more skeletal chain atoms selected from an atom other thancarbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinationsthereof.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. The polycyclicheteroaryl group may be fused or non-fused. Illustrative examples ofheteroaryl groups include the following moieties:

and the like.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four heteroatoms each selected from O, S and N,wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the ring of said group does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groupsinclude groups having only 4 atoms in their ring system, but aromaticheterocyclic groups must have at least 5 atoms in their ring system. Theheterocyclic groups include benzo-fused ring systems. An example of a4-membered heterocyclic group is azetidinyl (derived from azetidine). Anexample of a 5-membered heterocyclic group is thiazolyl. An example of a6-membered heterocyclic group is pyridyl, and an example of a10-membered heterocyclic group is quinolinyl. Examples of non-aromaticheterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups, as derived from the groups listedabove, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached)or pyrrol-3-yl (C-attached). Further, a group derived from imidazole maybe imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems and ring systems substituted with oneor two oxo (═O) moieties such as pyrrolidin-2-one.

A “heteroalicyclic” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Illustrative examplesof heterocycloalkyl groups include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

A “mercaptyl” group refers to a (alkyl)S— group.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “sulfinyl” group refers to a —S(═O)—R, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon)

A “sulfonyl” group refers to a —S(═O)₂—R, where R is selected from thegroup consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded througha ring carbon) and heteroalicyclic (bonded through a ring carbon)

A “thiocyanato” group refers to a —CNS group.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto,alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone,arylsulfone, cyano, halo, carbonyl, thiocarbonyl, isocyanato,thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, silyl,and amino, including mono- and di-substituted amino groups, and theprotected derivatives thereof. The protecting groups that may form theprotective derivatives of the above substituents are known to those ofskill in the art and may be found in references such as Greene and Wuts,above.

The compounds presented herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds having the structure ofFormula (A), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. In addition, the compounds described herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Certain Pharmaceutical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator whichenhances the activity of another molecule or the activity of a receptorsite.

The term “antagonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme inhibitor, or a hormone modulator, whichdiminishes, or prevents the action of another molecule or the activityof a receptor site.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

The term “bone disease,’ as used herein, refers to a disease orcondition of the bone, including, but not limited to, inapproriate boneremodeling, loss or gain, osteopenia, osteomalacia, osteofibrosis, andPaget's disease [Garcia, “Leukotriene B4 stimulates osteoclastic boneresorption both in intro and in vivo”, J Bone Miner Res.1996;11:1619-27].

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia; atherosclerosis and its sequelae; angina; myocardialischemia; myocardial infarction; cardiac or vascular aneurysm;vasculitis, stroke; peripheral obstructive arteriopathy of a limb, anorgan, or a tissue; reperfusion injury following ischemia of the brain,heart or other organ or tissue;endotoxic, surgical, or traumaticshock;hypertension, valvular heart disease,, heart failure, abnormal bloodpressure; shock; vasoconstriction (including that associated withmigraines); vascular abnormality, inflammation, insufficiency limited toa single organ or tissue. , [Lotzer K et al., “The 5-lipoxygenasepathway in arterial wall biology and atherosclerosis”, Biochim BiophysActa 2005;1736:30-7; Helgadottir A et al., “The gene encoding5-lipoxygenase activating protein confers risk of myocardial infarctionand stroke’, Nat Genet. 2004 March;36(3):233-9. Epub 2004 Feb. 8; [HeiseC E, Evans J F et al., “Characterization of the human cysteinylleukotriene 2 receptor”, J Biol Chem. 2000 Sep. 29;275(39):30531-6].

The term “cancer,’ as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma)or hematologist tumors (such as the leukemias) [Ding X Z et al., “Anovel anti-pancreatic cancer agent, LY293111”, Anticancer Drugs. 2005June;16(5):467-73. Review; Chen X et al., “Overexpression of5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitoryeffects of zileuton and celecoxib on carcinogenesis”, Clin Cancer Res.2004 Oct. 1;10(19):6703-9].

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “dermatological disorder,” as used herein refers to a skindisorder. Such dermatological disorders include, but are not limited to,proliferative or inflammatory disorders of the skin such as, atopicdermatitis, bullous disorders, collagenoses, contact dermatitis eczema,Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria [Wedi B etal., “Pathophysiological role of leukotrienes in dermatologicaldiseases: potential therapeutic implications”, BioDrugs.2001;15(11):729-43].

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “enzymatically cleavable linker,” as used herein refers tounstable or degradable linkages which may be degraded by one or moreenzymes.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that follow acute or chronic inflammation and are associatedwith the abnormal accumulation of cells and/or collagen and include butare not limited to fibrosis of individual organs or tissues such as theheart, kidney, joints, lung, or skin, and includes such disorders asidiopathic pulmonary fibrosis and cryptogenic fibrosing alveolitis[Charbeneau R P et al., “Eicosanoids: mediators and therapeutic targetsin fibrotic lung disease”, Clin Sci (Lond). 2005 June;108(6):479-91].

The term “iatrogenic” means a leukotriene-dependent orleukotriene-mediated condition, disorder, or disease created or worsenedby medical or surgical therapy.

The term “inflammatory disorders” refers to those diseases or conditionsthat are characterized by one or more of the signs of pain (dolor, fromthe generation of noxious substances and the stimulation of nerves),heat (calor, from vasodilatation), redness (rubor, from vasodilatationand increased blood flow), swelling (tumor, from excessive inflow orrestricted outflow of fluid), and loss of function (functio laesa, whichmay be partial or complete, temporary or permanent). Inflammation takesmany forms and includes, but is not limited to, inflammation that is oneor more of the following: acute, adhesive, atrophic, catarrhal, chronic,cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing,focal, granulomatous, hyperplastic, hypertrophic, interstitial,metastatic, necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative. Inflammatory disorders further include, without beinglimited to those affecting the blood vessels (polyarteritis, temporarlarteritis); joints (arthritis: crystalline, osteo-, psoriatic, reactive,rheumatoid, Reiter's); gastrointestinal tract (Disease,); skin(dermatitis); or multiple organs and tissues (systemic lupuserythematosus) [Harrison's Principles of Internal Medicine, 16^(th)Edition, Kasper D L, et al, Editors; McGraw-Hill, publishers].

The term “interstitial cystitis” refers to a disorder characterized bylower abdominal discomfort, frequent and sometimes painful urinationthat is not caused by anatomical abnormalites, infection, toxins, traumaor tumors [Bouchelouche K et al., “The cysteinyl leukotrine D4 receptorantagonst montelukast for the treatment of interstitial cystitis”, JUrol 2001;166:1734].

The term “leukotriene-driven mediators,” as used herein, refers tomolecules able to be produced in a patient that may result fromexcessive production of leukotriene stimulation of cells, such as, byway of example only, LTB₄, LTC₄, LTE₄, cysteinyl leuktorienes, monocyteinflammatory protein (MIP-1α), interleukin-8 (IL-8), interleukin-4(IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein(MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM),myeloperoxidase (MPO), eosinophil peroxidase (EPO), and generalinflammation molecules such as interleukin-6 (Il-6), C-reactive protein(CRP), and serum amyloid A protein (SAA).

The term “leukotriene-related mediators,” as used herein, refers tomolecules able to be produced in a patient that may be associated withexcessive production of leukotriene stimulation of cells, such as, byway of example only, LTB₄, LTC₄, LTE₄, cysteinyl leuktorienes, monocyteinflammatory protein (MIP-1α), interleukin-8 (IL-8), interleukin-4(IL-4), interleukin-13 (IL-13), monocyte chemoattractant protein(MCP-1), soluble intracellular adhesion molecule (sICAM; soluble ICAM),myeloperoxidase (MPO), eosinophil peroxidase (EPO), and generalinflammation molecules such as interleukin-6 (Il-6), C-reactive protein(CRP), and serum amyloid A protein (SAA).

The term “leukotriene-dependent”, as used herein, refers to conditionsor disorders that would not occur, or would not occur to the sameextent, in the absence of one or more leukotrienes.

The term “leukotriene-mediated”, as used herein, refers to refers toconditions or disorders that might occur in the absence of leukotrienesbut can occur in the presence of one or more leukotrienes.

The term “leukotriene-responsive patient,” as used herein, refers to apatient who has been identified by either genotyping of FLAP SNP orhaplotypes, or genotyping of one or more other genes in the leukotrienepathway and/or, by phenotyping of patients either by previous positiveclinical response to another leukotriene modulator, including, by way ofexample only, zileuton(Zyflo™), montelukast (Singulair™), pranlukast(Onon™), zafirlukast (Accolate™), and/or by their profile ofleukotriene-driven mediators that indicate excessive leukotrienestimulation of inflammatory cells, as likely to respond favorably toleukotriene modulator therapy.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Further information on metabolism may be obtainedfrom The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill(1996). Metabolites of the compounds disclosed herein can be identifiedeither by administration of compounds to a host and analysis of tissuesamples from the host, or by incubation of compounds with hepatic cellsin vitro and analysis of the resulting compounds. Both methods are wellknown in the art.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist and anantagonist.

The terms “neurogenerative disease” or “nervous system disorder,” asused herein, refers to conditions that alter the structure or functionof the brain, spinal cord or peripheral nervous system, including butnot limited to Alzheimer's Disease, cerebral edema, cerebral ischemia,multiple sclerosis, neuropathies, Parkinson's Disease, those found afterblunt or surgical trauma (including post-surgical cognitive dysfunctionand spinal cord or brain stem injury), as well as the neurologicalaspects of disorders such as degenerative disk disease and sciatica. Theacronym “CNS” refers to disorders of the central nervous system, i.e.,brain and spinal cord [Sugaya K, et al., “New anti-inflammatorytreatment strategy in Alzheimer's disease”, Jpn J Pharmacol. 2000February ;82(2):85-94; Yu G L, et al., “Montelukast, a cysteinylleukotriene receptor-1 antagonist, dose- and time-dependently protectsagainst focal cerebral ischemia in mice”, Pharmacology. 2005January;73(1):31-40. Epub 2004 Sep. 27; [Zhang W P, et al.,“Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist,on focal cerebral ischemia in rats’, Acta Pharmacol Sin. 2002October;23(10):871-7].

The terms “ocular disease” or “ophthalmic disease,” as used herein,refer to diseases which affect the eye or eyes and potentially thesurrounding tissues as well. Ocular or ophthalmic diseases include, butare not limited to, conjunctivitis, retinitis, scleritis, uveitis,allergic conjuctivitis, vernal conjunctivitis, pappillary conjunctivitis[Toriyama S., “Effects of leukotriene B4 receptor antagonist onexperimental autoimmune uveoretinitis in rats”, Nippon Ganka GakkaiZasshi. 2000 June; 104(6):396-40; [Chen F, et al., “Treatment of Santigen uveoretinitis with lipoxygenase and cyclo-oxygenase inhibitors”,Ophthalmic Res. 1991;23(2):84-91].

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutically acceptable salts may beobtained by reacting a compound of Formula (A) with acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticallyacceptable salts may also be obtained by reacting a compound of Formula(A) with a base to form a salt such as an ammonium salt, an alkali metalsalt, such as a sodium or a potassium salt, an alkaline earth metalsalt, such as a calcium or a magnesium salt, a salt of organic basessuch as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, and salts with amino acids such asarginine, lysine, and the like, or by other methods known in the art

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (1) and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula (1) and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (A) with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. Multiple techniques ofadministering a compound exist in the art including, but not limited to:intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary andtopical administration.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound of Formula (A) which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, trachea, bronchi, and lungs. Respiratory diseasesinclude, but are not limited to, asthma, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia [Evans J F, “The Cysteinyl Leukotriene (CysLT)Pathway in Allergic Rhinitis”, Allergology International2005;54:187-90); Kemp J P., “Leukotriene receptor antagonists for thetreatment of asthma”, IDrugs. 2000 April;3(4):430-41; Riccioni G, etal., “Effect of the two different leukotriene receptor antagonists,montelukast and zafirlukast, on quality of life: a 12-week randomizedstudy”, Allergy Asthma Proc. 2004 November-December;25(6):445-8].

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription. All references cited herein, including patents, patentapplications, and publications, are hereby incorporated by reference intheir entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 2 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 3 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 4 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 5 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 6 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 7 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 8 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 9 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 10 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 11 presents illustrative schemes for the syntheses of compoundsdescribed herein.

FIG. 12 presents illustrative examples of compounds described herein.

FIG. 13 presents illustrative examples of compounds described herein.

FIG. 14 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

FIG. 15 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

FIG. 16 present an illustrative scheme for the treatment of patientsusing the compounds and methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

Illustrative Biological Activity

Leukotrienes (LTs) are potent contractile and inflammatory mediatorsproduced by release of arachidonic acid from cell membranes andconversion to leukotrienes by the action of 5-lipoxygenase,5-lipoxygenase-activating protein, LTA₄ hydrolase and LTC₄ synthase. Theleukotriene synthesis pathway, or 5-lipoxygenase pathway, involves aseries of enzymatic reactions in which arachidonic acid is converted toleukotriene LTB₄, or the cysteinyl leukotrienes, LTC₄, LTD₄, and LTE₄.The pathway occurs mainly at the nuclear envelope and has beendescribed. See, e.g., Wood, J W et al, J. Exp. Med., 178: 1935-1946,1993; Peters-Golden, Am. J. Respir. Crit. Care Med. 157:S227-S232, 1998;Drazen, et al., ed. Five-Lipoxygenase Products in Asthma, Lung Biologyin Health and Disease Series, Vol. 120, Chs. 1, 2, and 7, Marcel Dekker,Inc. NY, 1998. Protein components dedicated to the leukotriene synthesispathway include a 5-lipoxygenase (5-LO), a 5-lipoxygenase-activatingprotein, a LTA4 hydrolase, and a LTC₄ synthase. The synthesis ofleukotrienes has been described in the literature, e.g., by Samuelssonet al, Science, 220, 568-575, 1983; Peters-Golden, “Cell Biology of the5-Lipoxygenase Pathway” Am J Respir Crit Care Med 157:S227-S232 (1998).Leukotrienes are synthesized directly from arachidonic acid by differentcells including eosinophils, neutrophils, basophils, lymphocytes,macrophages, monocytes and mast cells.,Excess LTA₄, for example from anactivated neutrophil, may enter a cell by a transcellular pathway. Mostcells in the body have LTA₄ hydrolase so can produce LTB₄. Platelets andendothelial cells have LTC₄ synthase, so can make LTC₄ when presentedwith LTA₄ by a transcellular pathway.

Arachidonic acid is a polyunsaturated fatty acid and is present mainlyin the membranes of the body's cells. Upon presentation of inflammatorystimuli from the exterior of the cell, calcium is released and binds tophospholipase A₂ (PLA2) and 5-LO. Cell activation results in thetranslocation of PLA₂ and 5-LO from the cytoplasm to the endoplasmicreticulum and/or nuclear membranes, where in the presence of FLAP, thereleased arachidonic acid is converted via a 5-HPETE intermediate to theepoxide LTA₄. Depending on the cell type, the LTA₄ may be immediatelyconverted to LTC₄ by the nuclear-bound LTC₄ synthase or to LTB₄ by theaction of cytosolic LTA₄ hydrolase. LTB₄ is exported from cells by an asyet uncharacterized transporter and may activate other cells, or thecell it was made in, via high affinity binding to one of two Gprotein-coupled receptors (GPCRs), namely BLT₁R or BLT₂R. LTC₄ isexported to the blood via the MRP-1 anion pump and rapidly converted toLTD₄ by the action of γ-glutamyl transpeptidase and LTD₄ is thenconverted to LTE₄ by the action of dipeptidases. LTC₄, LTD₄ and LTE₄ arecollectively referred to as the cysteinyl leukotrienes (or previously asslow reacting substance of anaphylaxis, SRS-A). The cysteinylleukotrienes activate other cells, or the cells they are made in, viahigh affinity binding to one of two GPCRs, namely CysLT₁R or CysLT₂R.CysLT₁ receptors are found in the human airway eosinophils, neutrophils,macrophages, mast cells, B-lymphocytes and smooth muscle and inducebronchoconstriction. Zhu et al, Am J Respir Cell Mol Biol Epub Aug. 25(2005). CysLT₂ receptors are located in human airway eosinophils,macrophages, mast cells the human pulmonary vasculature Figueroa et al,Clin Exp Allergy 33:1380-1388 (2003).

Involvement of Leukotrienes in Diseases or Conditions

The involvement of leukotrienes in disease is described in detail in theliterature. See e.g., by Busse, Clin. Exp. Allergy 26:868-79, 1996;O'Byrne, Chest 111 (Supp. 2): 27S-34S, 1977; Sheftell, F. D., et al.,Headache, 40:158-163, 2000; Klickstein et al., J. Clin. Invest.,66:1166-1170, 1950; Davidson et al., Ann. Rheum. Dis., 42:677-679, 1983Leukotrienes produce marked inflammatory responses in human skin.Evidence for the involvement of leukotrienes in a human disease is foundin psoriasis, in which leukotrienes have been detected in psoriaticlesions (Kragballe et al., Arch. Dermatol., 119:548-552, 1983).

For example, inflammatory responses have been suggested to reflect threetypes of changes in the local blood vessels. The primary change is anincrease in vascular diameter, which results in an increase in localblood flow and leads to an increased temperature, redness and areduction in the velocity of blood flow, especially along the surfacesof small blood vessels. The second change is the activation ofendothelial cells lining the blood vessel to express adhesion moleculesthat promote the binding of circulating leukocytes. The combination ofslowed blood flow and induced adhesion molecules allows leukocytes toattach to the endothelium and migrate into the tissues, a process knownas extravasation. These changes are initiated by cytokines andleukotrienes produced by activated macrophages. Once inflammation hasbegun, the first cells attracted to the site of infection are generallyneutrophils. They are followed by monocytes, which differentiate intomore tissue macrophages. In the latter stages of inflammation, otherleukocytes, such as eosinophils and lymphocytes also enter the infectedsite. The third major change in the local blood vessels is an increasein vascular permeability. Instead of being tightly joined together, theendothelial cells lining the blood vessel walls become separated,leading to exit of fluid and proteins from the blood and their localaccumulation in the tissue. (See Janeway, et al., Immunobiology: theimmune system in health and disease, 5th ed., Garland Publishing, NewYork, 2001)

LTB₄ produces relatively weak contractions of isolated trachea and lungparenchyma, and these contractions are blocked in part by inhibitors ofcyclooxygenase, suggesting that the contraction are secondary to therelease of prostaglandins. However, LTB₄ has been shown to be a potentchemotactic agent for eosinophils and progenitors of mast cells and theLTB₄ receptor BLT1−/− knockout mouse is protected from eosinophilicinflammation and T-cell mediated allergic airway hyperreactivity.Miyahara et al J Immunol 174:4979-4784; (Weller et al J Exp Med201:1961-1971(2005).

Leukotrienes C₄ and D₄ are potent smooth muscle contractile agents,promoting bronchoconstriction in a variety of species, including humans(Dahlen et al., Nature, 288:484-486, 1980). These compounds haveprofound hemodynamic effects, constricting coronary blood vessels, andresulting in a reduction of cardiac output efficiency (Marone et al., inBiology of Leukotrienes, ed. By R. Levi and R. D. Krell, Ann. New YorkAcad. Sci. 524:321-333, 1988). Leukotrienes also act asvasoconstrictors, however, marked differences exist for differentvascular beds. There are reports suggesting that leukotrienes contributeto cardiac reperfusion injury following myocardial ischemia (Barst andMullane, Eur. J. Pharmacol., 114: 383-387, 1985; Sasaki et al.,Cardiovasc. Res., 22: 142-148, 1988). LTC₄ and LTD₄ directly increasevascular permeability probably by promoting retraction of capillaryendothelial cells via activation of the CysLT₂ receptor and possiblyother as yet undefined CysLT receptors [Lotzer et al Arterioscler ThrombVasc Biol 23: e32-36.(2003)]. LTB₄ enhances atherosclerotic progressionin two atherosclerotic mouse models, namely low density receptorlipoprotein receptor deficient (LDLr−/−) and apolipoprotein E-deficient(ApoE−/−) mice (Aiello et al, Arterioscler Thromb Vasc Biol 22:443-449(2002); Subbarao et al, Arterioscler Thromb Vasc Biol 24:369-375 (2004);Heller et al Circulation 112:578-586 (2005). LTB₄ has also been shown toincrease human monocyte chemoattractant protein (MCP-1) a known enhancerof atherosclerotic progression (Huang et al Aterioscler Thromb Vasc Biol24:1783-1788 (2004).

The role of FLAP in the leukotriene synthesis pathway is significantbecause FLAP in concert with 5-lipoxygenase performs the first step inthe pathway for the synthesis of leukotrienes. Therefore the leukotrienesynthesis pathway provides a number of targets for compounds useful inthe treatment of leukotriene-dependent or leukotriene mediated diseasesor conditions, including, by way of example, vascular and inflammatorydisorders, proliferative diseases, and non-cancerous disorders.

Leukotriene-dependent or leukotriene mediated conditions treated usingthe methods, compounds, pharmaceutical compositions and medicamentsdescribed herein, include, but are not limited to, bone diseases anddisorder, cardiovascular diseases and disorders, inflammatory diseasesand disorders, dermatological diseases and disorders, ocular diseasesand disorders, cancer and other proliferative diseases and disorders,respiratory diseases and disorder, and non-cancerous disorders.

Treatment Options

Leukotrienes are known to contribute to the inflammation of the airwaysof patients with asthma. CysLT₁ receptor antagonists such as montelukast(Singulair™) have been shown to be efficacious in asthma and allergicrhinitis [Reiss et al. Arch Intern Med 158:1213-1220 (1998); Phillip etal Clin Exp Allergy 32:1020-1028 (2002)]. CysLT₁R antagonists pranlukast(Onon™) and zafirlukast (Accolate™) have also been shown to beefficacious in asthma.

A number of drugs have been designed to inhibit leukotriene formation,including the 5-lipoxygenase inhibitor zileuton (Zyflo™) that has shownefficacy in asthma, Israel et al Ann Intern Med 119:1059-1066 (1993).The 5-lipoxygenase inhibitor ZD2138 showed efficacy in inhibiting thefall of FEV1 resulting from aspirin-induced asthma, Nasser et al,Thorax, 49; 749-756 (1994). The following leukotriene synthesisinhibitors have shown efficacy in asthma: MK-0591, a specific inhibitorof 5-lipoxygenase-activating protein (FLAP), Brideau, et al, Ca. J.Physiol. Pharmacol. 70:799-807 (1992), MK-886, a specific inhibitor of5-lipoxygenase-activating protein (FLAP), Friedman et al Am Rev RespirDis., 147: 839-844 (1993), and BAY X1005, a specific inhibitor of5-lipoxygenase-activating protein (FLAP), Fructmann et al, AgentsActions 38: 188-195 (1993).

FLAP inhibition will decrease LTB₄ from monocytes, neutrophils and othercells involved in vascular inflammation and thereby decreaseatherosclerotic progression. The FLAP inhibitor MK-886 has been shown toto decrease the postangioplasty vasoconstrictive response in a porcinecarotid injury model Provost et al Brit J Pharmacol 123: 251-258 (1998).MK-886 has also been shown to suppress femoral artery intimalhyperplasia in a rat photochemical model of endothelial injury Kondo etal Thromnb Haemost 79:635-639 (1998). The 5-lipoxygenase inhibitorzileuton has been shown to reduce renal ischemia in a mouse model,Nimesh et al Mol Pharm 66:220-227 (2004).

FLAP modulators have been used for the treatment of a variety ofdiseases or conditions, including, by way of example only, (i)inflammation (see e.g. Leff A R et al., “Discovery of leukotrienes andthe development of antileukotriene agents”, Ann Allergy Asthma Immunol2001;86 (Suppl 1)4-8; Riccioni G, et al., “Advances in therapy withantileukotriene drugs”, Ann Clin Lab Sci. 2004, 34(4):379-870; (ii)respiratory diseases including asthma, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma (see e.g. Riccioni et al, Ann.Clin. Lab. Sci., v34, 379-387 (2004)); (iii) chronic obstructivepulmonary disease, including chronic bronchitis or emphysema, pulmonaryhypertension, interstitial lung fibrosis and/or airway inflammation andcystic fibrosis (see e.g. Kostikas K et al., “Leukotriene V4 in exhaledbreath condensate and sputum supernatant in patients with COPD andasthma”, Chest 2004;127:1553-9); (iv) increased mucosal secretion and/oredema in a disease or condition (see e.g. Shahab R et al.,“Prostaglandins, leukotrienes, and perennial rhinitis”, J LaryngolOtol., 2004;118;500-7); (v) vasoconstriction, atherosclerosis and itssequelae myocardial ischemia, myocardial infarction, aortic aneurysm,vasculitis and stroke (see e.g. Jala et al, Trends in Immunol., v25,315-322 (2004) and Mehrabian et al, Curr. Opin. Lipidol., v14, 447-457(2003)); (vi) reducing organ reperfusion injury following organ ischemiaand/or endotoxic shock (see e.g. Matsui N, Fukuishi N, Fukuyama Y, YasuiY, Akagi M., “Protective effect of the 5-lipoxygenase inhibitorardisiaquinone A on hepatic ischemia-reperfusion injury in rats”, PlantaMed. 2005 August;71(8):717-20); (vii) reducing the constriction of bloodvessels (see e.g. Stanke-Labesque F et al., “Inhibition of leukotrienesynthesis with MK-886 prevents a rise in blood pressure and reducesnoradrenaline-evoked contraction in L-NAME-treated rats”, Br JPharmacol. 2003 September;140(1):186-94); (viii) lowering or preventingan increase in blood pressure (see e.g. Stanke-Labesque F et al.,“Inhibition of leukotriene synthesis with MK-886 prevents a rise inblood pressure and reduces noradrenaline-evoked contraction inL-NAME-treated rats”, Br J Pharmacol. 2003 September; 140(1):186-94, andWalch L, Norel X, Back M, Gascard J P, Dahlen S E, Brink C.,“Pharmacological evidence for a novel cysteinyl-leukotriene receptorsubtype in human pulmonary artery smooth muscle”, Br J Pharmacol. 2002December; 137(8):1339-45); (ix) preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte recruitment (seee.g. Miyahara N, Takeda K, Miyahara S, Taube C, Joetham A, Koya T,Matsubara S, Dakhama A, Tager A M, Luster A D, Gelfand E W.,“Leukotriene B4 receptor-1 is essential for allergen-mediatedrecruitment of CD8+ T cells and airway hyperresponsiveness”, Immunol.2005 Apr. 15;174(8):4979-84); (x) abnormal bone remodeling, loss orgain, including osteopenia, osteoporosis, Paget's disease, cancer andother diseases (see e.g. Anderson G I, MacQuarrie R, Osinga C, Chen Y F,Langman M, Gilbert R., “Inhibition of leukotriene function can modulateparticulate-induced changes in bone cell differentiation and activity”,Biomed Mater Res. 2001;58(4):406-140; (xi) ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis (see e.g. Lambiase et al, Arch. Opthalmol., v121, 615-620(2003)); (xii) CNS disorders, including, but are not limited to,multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke,cerebral ischemia, retinal ischemia, post-surgical cognitivedysfunction, migraine (see e.g. de Souza Carvalho D, Fragoso Y D, CoelhoF M, Pereira M M., “Asthma plus migraine in childhood and adolescence:prophylactic benefits with leukotriene receptor antagonist”, Headache.2002 November-December;42(10):1044-7; Sheftell F, Rapoport A, Weeks R,Walker B, Gammerman I, Baskin S., “Montelukast in the prophylaxis ofmigraine: a potential role for leukotriene modifiers”, Headache. 2000February;40(2):158-63); (xiii) peripheral neuropathy/neuropathic pain,spinal cord injury (see e.g. Akpek E A, Bulutcu E, Alanay A, Korkusuz P,Acaroglu E, Kilinc K, Ors U., “A study of adenosine treatment inexperimental acute spinal cord injury. Effect on arachidonic acidmetabolites”, Spine. 1999 Jan. 15;24(2):128-32), cerebral edema and headinjury; (xiv) cancer, including, but is not limited to, pancreaticcancer and other solid or hematological tumors, (see e.g. Poff andBalazy, Curr. Drug Targets Inflamm. Allergy, v3, 19-33 (2004) and Steeleet al, Cancer Epidemiology & Prevention, v8, 467-483 (1999); (xv)endotoxic shock and septic shock (see e.g. Leite M S, Pacheco P, Gomes RN, Guedes A T, Castro-Faria-Neto H C, Bozza P T, Koatz V L., “Mechanismsof increased survival after lipopolysaccharide-induced endotoxic shockin mice consuming olive oil-enriched diet”, Shock. 2005February;23(2):173-8); (xvi) rheumatoid arthritis and osteoarthritis(see e.g. Alten R, Gromnica-Ihle E, Pohl C, Emmerich J, Steffgen J,Roscher R, Sigmund R, Schmolke B, Steinmann G., “Inhibition ofleukotriene B₄-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a newlong acting LTB₄ receptor antagonist, in patients with rheumatoidarthritis”, Ann Rheum Dis. 2004 February;63(2):170-6); (xvii) preventingincreased GI diseases, including, by way of example only, chronicgastritis, eosinophilic gastroenteritis, and gastric motor dysfunction,(see e.g. Gyomber et al, J Gastroenterol Hepatol., v11,922-927 (1996);Quack I et al BMC Gastroenterol v18,24 (2005); Cuzzocrea S, Rossi A,Mazzon E, Di Paola R, Genovese T, Muia C, Caputi A P, Sautebin L.,“5-Lipoxygenase modulates colitis through the regulation of adhesionmolecule expression and neutrophil migration”, Lab Invest. 2005 June;85(6):808-22); (xviii) kidney diseases, including, by way of exampleonly, glomerulonephritis, cyclosporine nephrotoxicity renal ischemiareperfusion. (see e.g. Guasch et al Kidney Int., v56, 261-267; Butterlyet al, v 57, 2586-2593 (2000); Guasch A et al. “MK-591 acutely restoresglomerular size selectivity and reduces proteinuria in humanglomerulonephritis”, Kidney Int. 1999; 56:261-7; Butterly D W et al. “Arole for leukotrienes in cyclosporine nephrotoxicity”, Kidney Int. 2000;57:2586-93); (xix) preventing or treating acute or chronic renalinsufficiency (see e.g. Maccarrone M, et al., “Activation of5-lipoxygenase and related cell membrane lipoperoxidation inhemodialysis patients”, J Am Soc Nephrol. 1999; 10:1991-6); (xx) type IIdiabetes (see e.g. Valdivielso et al, v16, 85-94 (2003); (xxi) dimnishthe inflammatory aspects of acute infections within one or more solidorgans or tissues such as the kidney with acute pyelonephritis (see e.g.Tardif M, Beauchamp D, Bergeron Y, Lessard C, Gourde P, Bergeron M G.L-651,392, “A potent leukotriene inhibitor, controls inflammatoryprocess in Escherichia coli pyelonephritis”, Antimicrob AgentsChemother. 1994 July; 38(7):1555-60); (xxii) preventing or treatingacute or chronic disorders involving recruitment or activation ofeosinophils (see e.g. Quack I, e al. “Eosinophilic gastroenteritis in ayoung girl—long term remission under montelukast”, BMC Gastroenterol.,2005; 5:24; (xxiii) preventing or treating acute or chronic erosivedisease or motor dysfunction of the gastrointestinal tract caused bynon-steroidal anti-inflammatory drugs (including selective ornon-selective cyclooxygenase-1 or -2 inhibitors) (see e.g. Marusova I B,et al., “Potential gastroprotective effect of a CysLT1 receptor blockersodium montelukast in aspirin-induced lesions of the rat stomachmucosa”, Eksp Klin Farmakol, 2002; 65:16-8 and Gyomber E, et al.,“Effect of lipoxygenase inhibitors and leukotriene antagonists on acuteand chronic gastric haemorrhagic mucosal lesions in ulcer models in therat”, J. Gastroenterol. Hepatol., 1996, 11, 922-7) and Martin St et al.,“Gastric motor dysfunction: is eosinophilic mural gastritis a causativefactor?”, Eur J Gastroenterol. Hepatol., 2005, 17:983-6; (xxiv) treatingtype II diabetes (see e.g. Valdivielso J M, Montero A, Badr K F, MungerK A., “Inhibition of 5-lipoxygenase activating protein decreasesproteinuria in diabetic rats”, J Nephrol. 2003 January-February;16(1):85-94; Parlapiano C, Danese C, Marangi M, Campana E, Pantone P,Giovanniello T, Zavattaro E, Sanguigni S., “The relationship betweenglycated hemoglobin and polymorphonuclear leukocyte leukotriene B4release in people with diabetes mellitus”, Diabetes Res Clin Pract. 1999October; 46(1):43-5; (xxv) treatment of metabolic syndromes, including,by way of example only, Familial Mediterranean Fever (see e.g. BentancurA G, Naveh N, Lancri J, Selah B A, Livneh A., “Urine leukotriene B4 infamilial Mediterranean fever”, Clin Exp Rheumatol. 2004 July-August;22(4 Suppl 34):S56-8; and (xxvi) treat hepatorenal syndrome (see e.g.Capella G L., “Anti-leukotriene drugs in the prevention and treatment ofhepatorenal syndrome”, Prostaglandins Leukot Essent Fatty Acids. 2003April;68(4):263-5].

Several inhibitors of FLAP have been described (Gillard et al, Can. J.Physiol. Pharmacol., 67, 456-464, 1989; Evans et al, MolecularPharmacol., 40, 22-27, 1991; Brideau et al, Can. J. Physiol. Pharmacol.,Musser et al, J. Med. Chem., 35, 2501-2524, 1992; Steinhilber, Curr.Med. Chem. 6(1):71-85, 1999; Riendeau, Bioorg Med Chem Lett.,15(14):3352-5, 2005; Flamand, et al., Mol. Pharmacol. 62(2):250-6, 2002;Folco, et al., Am. J. Respir. Crit. Care Med. 161(2 Pt 2):S112-6, 2000;Hakonarson, JAMA, 293(18):2245-56, 2005).

Identification of Leukotriene Synthesis Pathway Inhibitors

The development and testing of novel FLAP inhibitors which are effectiveeither alone or in combination with other drugs, and which result inminimal negative side effects would be beneficial for treatingleukotriene-dependent or leukotriene mediated diseases or conditions.Inhibitors of the leukotriene synthesis pathway described herein maytarget any step of the pathway to prevent or reduce the formation ofleukotrienes. Such leukotriene synthesis inhibitors can, by way ofexample, inhibit at the level of FLAP, or 5-LO, thus minimizing theformation of various products in the leukotriene pathway, therebydecreasing the amounts of such compounds available in the cell.Leukotriene synthesis inhibitors can be identified based on theirability to bind to proteins in the leukotriene synthesis pathway. Forexample, FLAP inhibitors can be identified based on their binding toFLAP.

Compounds

Compounds of Formula (A):

Compounds of Formula (A), pharmaceutically acceptable salts,pharmaceutically acceptable N-oxides, pharmaceutically activemetabolites, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable solvates thereof, antagonize or inhibit FLAP and may be usedto treat patients suffering from leukotriene-dependent or leukotrienemediated conditions or diseases, including, but not limited to, asthma,myocardial infarction, cancer, and inflammatory conditions;

wherein,

-   each A is independently selected from N or CR₅, and each A′ is    C-Z-Y, N or CR₅, provided that one A′ is C-Z-Y and the other A′ is N    or CR₅ and provided that the number of N groups from A plus the    number of N groups from A′ is 1 or 2;-   Z is selected from a bond, CR₁═CR₁, —C≡C—, C(R₂)_(n), C(R₁)₂O,    OC(R₁)₂, C(R₁)₂S(O)_(m), S(O)_(m)C(R₁)₂, C(R₁)₂NH, NHC(R₁)₂,    C(R₂)₂C(R₁)₂O, C(R₁)₂OC(R₁)₂, OC(R₁)₂C(R₂)₂, C(O)NH, NHC(O), wherein    each R₁ is independently H, CF₃, or an optionally substituted lower    alkyl; and each R₂ is independently H, OH, OMe, CF₃, or an    optionally substituted lower alkyl; m is 0, 1 or 2; n is 0, 1, 2, or    3;-   Y is a -L₁-(substituted or unsubstituted heterocycle),    -L₁-(substituted or unsubstituted heteroaryl), -L₁-(substituted or    unsubstituted aryl) or -L₁-C(═NR₃)N(R₄)₂, -L₁-NC(═NR₃)N(R₄)₂,    -L₁-NR₄C(═CR₃)N(R₄)₂;    -   where R₃ is independently selected from H, —S(═O)₂R₄,        —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂, heteroaryl, or heteroalkyl;    -   each R₄ is independently selected from H, substituted or        unsubstituted lower alkyl, substituted or unsubstituted lower        cycloalkyl;    -   or two R₄ groups can together form a 5-, 6-, 7-, or 8-membered        heterocyclic ring; and    -   or R₃ and R₄ groups can together form a 5-, 6-, 7-, or        8-membered heterocyclic ring;    -   where L₁ is a bond, a substituted or unsubstituted alkyl, a        substituted or unsubstituted alkenyl, a substituted or        unsubstituted alkynyl, a substituted or unsubstituted        heteroalkyl;-   R₆ is H, L₂-(substituted or unsubstituted alkyl), L₂-(substituted or    unsubstituted cycloalkyl), L₂-(substituted or unsubstituted    alkenyl), L₂-(substituted or unsubstituted cycloalkenyl),    L₂-(substituted or unsubstituted heterocycle), L₂-(substituted or    unsubstituted heteroaryl), or L₂-(substituted or unsubstituted    aryl), where L₂ is a bond, O, S, —S(═O), —S(═O)₂, C(O),    -(substituted or unsubstituted C₁-C₆ alkyl), or -(substituted or    unsubstituted C₂-C₆ alkenyl);-   R₇ is L₃-X-L₄-G, wherein,-   X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),    —C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,    —NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—,    —ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,    —NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—;-   L₃ is a bond, substituted or unsubstituted alkyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,    substituted or unsubstituted alkynyl, substituted or unsubstituted    aryl, substituted or unsubstituted heteroaryl, substituted or    unsubstituted heterocycle;-   L₄ is a bond, optionally substituted or unsubstituted alkyl,    optionally substituted or unsubstituted cycloalkyl, optionally    substituted or unsubstituted alkenyl, optionally substituted or    unsubstituted alkynyl;-   G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,    —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,    —C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,    —C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or    unsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),    -L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted    or unsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH,    —C(O)O, or —OC(O);-   or G is W-G₁, where W is a substituted or unsubstituted aryl,    substituted or unsubstituted heterocycle or substituted or    unsubstituted heteroaryl and G₁ is H, —CO2H, tetrazolyl,    —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈,    —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂,    —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂, —CONHR₈, or —CON(R₈)₂;-   each R₈ is independently selected from substituted or unsubstituted    lower alkyl, substituted or unsubstituted lower cycloalkyl;-   each R₉ is independently selected from H, substituted or    unsubstituted lower alkyl, substituted or unsubstituted lower    cycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or    8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-,    6-, 7-, or 8-membered heterocyclic ring and-   each R₁₀ is independently selected from H, —S(═O)₂R₈,    —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, or heteroalkyl;-   R₅ is H, halogen, —N₃, —CN, —ONO₂, -L₆-(substituted or unsubstituted    C₁-C₃ alkyl), -L₆-(substituted or unsubstituted C₂-C₄ alkenyl),    -L₆-(substituted or unsubstituted heteroaryl), or -L₆-(substituted    or unsubstituted aryl), wherein L₆ is a bond, O, S, —S(═O), S(═O)₂,    NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), —C(O)NH;-   R₁₁ is L₇-G, L₇-(substituted or unsubstituted cycloalkyl)-G,    L₇-(substituted or unsubstituted cycloalkenyl)-G, L₇-(substituted or    unsubstituted heteroaryl)-G, or L₇-(substituted or unsubstituted    aryl )-G, L₇-(substituted or unsubstituted heterocycle)-G, where L₇    is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆    alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl);-   R₁₂ is H, or L₈-L₉-R₁₃, wherein L₈ is a bond, (substituted or    unsubstituted C₁-C₆ alkyl), or (substituted or unsubstituted C₂-C₄    alkenyl); L₉ is a bond, O, S, —S(═O), S(═O)₂, NH, C(O), —NHC(O)O,    —OC(O)NH, —NHC(O)—, —C(O)NH—, —C(O)O—, or —OC(O)—; R₁₃, is H,    (substituted or unsubstituted C₁-C₆ alkyl), (substituted or    unsubstituted aryl), (substituted or unsubstituted heteroaryl), or    (substituted or unsubstituted heterocycle);-   or R₇ and R₁₂ can together form a 4 to 8-membered heterocyclic ring.

In a further or alternative embodiment, the “G” group of Formula (A) isany group that is used to tailor the physical and biological propertiesof the molecule. Such tailoring/modifications are achieved using groupswhich modulate acidity, basicity, lipophilicity, solubility and otherphysical properties of the molecule. The physical and biologicalproperties modulated by such modifications to G include, by way ofexample only, solubility, in vivo absorption, and in vivo metabolism. Inaddition, in vivo metabolism may include, by way of example only,controlling in vivo PK properties, off-target activities, potentialtoxicities associated with cypP450 interactions, drug-drug interactions,and the like. Further, modifications to G allow for the tailoring of thein vivo efficacy of the compound through the modulation of, by way ofexample, specific and non-specific protein binding to plasma proteinsand lipids and tissue distribution in vivo. Additionally, suchtailoring/modifications to G allow for the design of compounds selectivefor 5-lipoxygenase-activating protein over other proteins.

In further or alternative embodiments, G is L₂₀-Q, wherein L₂₀ is anenzymatically cleavable linker and Q is a drug, or an affinity moiety.In further or alternative embodiments, the drug includes, by way ofexample only, leukotriene receptor antagonists and anti-inflammatoryagents. In further or alternative embodiments, the leukotriene receptorantagonists include, but are not limited to, CysLT1/CysLT2 dualantagonists and CysLT1 antagonists. In further or alternativeembodiments, the affinity moiety allow for site specific binding andinclude, but are not limited to, antibodies, antibody fragments, DNA,RNA, siRNA, and ligands.

Additional embodiments of Formula (A) are shown below as Formula (B),Formula (C), Formula (D), Formula (E), Formula (F), and Formula (G):

In further or alternative embodiments, the

is selected from the group consisting of quinolinyl, isoquinolinyl,pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolyl,benzothiazolyl, thiazolopyridinyl, oxazolyl, benzoxazolyl,oxazolopyridinyl, thiazolopyrimidinyl, oxazolopyrimidinyl, benzoxazinyl,and benzothiazinyl.

Additional embodiments of Formula (A) are shown below as Formula (I),Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI),Formula (VII) Formula (VIII), Formula (IX), Formula (X), Formula (XI),Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula(XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX),Formula (XXI), Formula (XXII), Formula (XXIII) and Formula (XXIV).

Additionally, each of such embodiments further include embodiments inwhich the

moiety is selected from the group consisting of

Further embodiments of Formula (A) include, but are not limited to, thecompounds shown in FIG. 12 and FIG. 13.

Synthesis of Compounds of Formula (A)

Compounds of Formula (A) and compounds having the structures describedin the prior section may be synthesized using standard synthetictechniques known to those of skill in the art or using methods known inthe art in combination with methods described herein. In additions,solvents, temperatures and other reaction conditions presented hereinmay vary according to those of skill in the art.

The starting material used for the synthesis of the compounds of Formula(A) and compounds having the structures described in the prior sectionmay be synthesized or can be obtained from commercial sources, such asAldrich Chemical Co. (Milwaukee, Wis.), or Sigma Chemical Co. (St.Louis, Mo.). The compounds described herein, and other related compoundshaving different substituents can be synthesized using techniques andmaterials known to those of skill in the art, such as described, forexample, in March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992);Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B(Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 3^(rd) Ed., (Wiley 1999) (all of which are incorporated byreference in their entirety). General methods for the preparation ofcompound as disclosed herein may be derived from known reactions in thefield, and the reactions may be modified by the use of appropriatereagents and conditions, as would be recognized by the skilled person,for the introduction of the various moieties found in the formulae asprovided herein. As a guide the following synthetic methods may beutilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. Table 1 entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups. TABLE 1 Examples of Covalent Linkages andPrecursors Thereof Covalent Linkage Product Electrophile NucleophileCarboxamides Activated esters amines/anilines Carboxamides acyl azidesamines/anilines Carboxamides acyl halides amines/anilines Esters acylhalides alcohols/phenols Esters acyl nitriles alcohols/phenolsCarboxamides acyl nitriles amines/anilines Imines Aldehydesamines/anilines Hydrazones aldehydes or ketones Hydrazines Oximesaldehydes or ketones Hydroxylamines Alkyl amines alkyl halidesamines/anilines Esters alkyl halides carboxylic acids Thioethers alkylhalides Thiols Ethers alkyl halides alcohols/phenols Thioethers alkylsulfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alkylsulfonates alcohols/phenols Esters Anhydrides alcohols/phenolsCarboxamides Anhydrides amines/anilines Thiophenols aryl halides ThiolsAryl amines aryl halides Amines Thioethers Azindines Thiols Boronateesters Boronates Glycols Carboxamides carboxylic acids amines/anilinesEsters carboxylic acids Alcohols hydrazines Hydrazides carboxylic acidsN-acylureas or carbodiimides carboxylic acids Anhydrides Estersdiazoalkanes carboxylic acids Thioethers Epoxides Thiols Thioethershaloacetamides Thiols Ammotriazines halotriazines amines/anilinesTriazinyl ethers halotriazines alcohols/phenols Amidines imido estersamines/anilines Ureas Isocyanates amines/anilines Urethanes Isocyanatesalcohols/phenols Thioureas isothiocyanates amines/anilines ThioethersMaleimides Thiols Phosphite esters phosphoramidites Alcohols Silylethers silyl halides Alcohols Alkyl amines sulfonate estersamines/anilines Thioethers sulfonate esters Thiols Esters sulfonateesters carboxylic acids Ethers sulfonate esters Alcohols Sulfonamidessulfonyl halides amines/anilines Sulfonate esters sulfonyl halidesphenols/alcoholsUse of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Protecting groups are used toblock some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. Protective groups can be removed by acid, base, andhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd₀-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference in their entirety.

A non-limiting example of a synthetic approach toward compounds ofFormula (B) is shown according to reaction Scheme IA in FIG. 1.Pyrrolo-pyridines of the Formula (IA-6) may be prepared starting fromcommercially available 2-amino-5-chloropyridine (IA-1). Iodination usingAg(I) salts and iodine furnishes iodo-pyridine (IA-2; see Cooper et. al.Bioorg. Med. Chem. Lett. 2001, 11, 1233). Palladium mediated crosscoupling of a suitably substituted alkyne under basic conditionsconstructs the pyrrolo-pyridine nucleus (IA-3) (see Park et. al.Tetrahedron Lett. 1998, 39, 627; Barber and Dickinson, Bioorg. Med.Chem. Lett. 2002, 12, 185; Koradin et. al. Tetrahedron, 2003, 59, 1571and references cited therein). Alkylation of the pyrrolo-pyridinenitrogen using a variety of substituted alkyl halides, mesylates ortosylate, or the like, under standard conditions using appropriate basesand solvents yields IA-4, which may then be substituted at the3-position with a variety of electrophiles (see Prasit et. al. U.S. Pat.No. 5,204,344; Dillard et. al. J. Med. Chem. 1996, 39, 5119 for example)to give IA-5. Transformation of the aryl-chloride functionality of IA-5under thermal or metal mediated catalysis affords the desired targetsIA-6. If the reaction conditions needed for the introduction offunctionalities at the 3-position are incompatible with substrates suchas IA-4, by way of example, addition of thio groups at the 3-position ofindoles (see Atkinson et. al. Synthesis, 1988, 480 and references citedtherein), then strong bases with an appropriate electrophile may bereacted with IA-3 yielding the pyrrolo-pyridine (IA-7). The freenitrogen of IA-7 may then be substituted vide supra to give IA-8, whichmay then be converted to the target molecules as described.

Alternatively, a non-limiting example of a synthetic approach towardcompounds of Formula (B) is shown according to reaction Scheme IB inFIG. 1. Pyrrolo-pyridines of Formula (IB-7) may be prepared startingwith commercially available 5-iodo-2-aminopyridine (IB-1) by conversionto the 5-alkoxy derivative (IB-4) using alcohol R₈OH under either asodium/copper couple (Trapani et. al. J. Med. Chem. 1997, 40, 3109) orcopper catalyzed coupling as described by Buchwald et. al. (Org. Lett.2002, 4, 973). Transformation to the hydrazine derivative (IB-5) isachieved by diazotization and reduction of the intermediate usingconditions well known in the art. Fischer indolization under standardconditions affords the pyrrolo-pyridine intermediate (IB-6) which isreadily alkylated with a variety of substituted alkyl halides, mesylatesor tosylates, and the like under standard conditions using appropriatebases and solvents to yield compounds of Formula (IB-7). Alternatively,pyrrolo-pyridines of Formula (IB-7) may be prepared by converted5-iodo-2-aminopyridine (I-1) to the hydrazine derivative (IB-2) videsupra, which can then be converted to the 5-iodo-pyrrolo-pyridinederivative (IB-3) by Fischer indolization. As described above, this iodofunctionality can be converted to the alkoxy derivatized compounds ofFormula (IB-7) using an appropriately substituted alcohol under metalmediated catalysis. For example, transition metal catalyzed crosscoupling reactions that are well known to those experienced in the artof organic chemistry provide access to a wide range of substitutedproducts. Such chemistry is described in Comprehensive OrganometallicChemistry II, vol 12, Pergamon, edited by Abel, Stone and Wilkinson.

A further non-limiting example of a synthetic approach toward methoxyderivatives of compounds of Formula (B) is shown as reaction Scheme II,in FIG. 2. The methoxy derivative (II-6) (see Scheme I, R₈=Me) may beprepared starting from commercially available 2-amino-5-iodopyridine(II-1). Conversion to the 5-methoxy derivative (II-2) using either asodium/copper couple (Trapani et. al. J. Med. Chem. 1997, 40, 3109) orthrough metal mediated catalysis (Wolter et. al. Org. Lett. 2002, 4,973) followed by introduction of the iodide function as previouslydiscussed affords II-3. Palladium mediated coupling of a suitablysubstituted alkyne and ring closure vide supra furnishes thepyrrolo-pyridine core (II-4). This may be manipulated as described inscheme I, to yield the methoxy pyrrolo-pyridine (II-5), which can thenbe alkylated at the pyrrolo-pyridine nitrogen using a variety ofsubstituted alkyl halides, mesylates or tosylate, or the like, understandard conditions using appropriate bases and solvents to yield themethoxy derivative (II-6). De-methylation of (II-6) reveals the alcohol(II-7) (see Brooks et. al. U.S. Pat. No. 5,288,743) which in turn may besuitably alkylated to produce the required pyrrolo-pyridine structures(II-8) (see Frenette et. al. Bioorg. Med. Chem. Lett. 1999, 9, 2391,examples of suitable alkylating agents can be found in U.S. Pat. No.5,314,900). The phenol intermediate (II-7) may also be transformed tothe triflate (II-9) under standard conditions to facilitate theintroduction of a variety of substituents through metal mediated crosscoupling chemistry yielding the target molecules (II-10).

A non-limiting example of a synthetic approach toward compounds ofFormula (C) is shown according to reaction Scheme III in FIG. 3. Thepyrrolo-pyridine derivatives may be prepared by initial protection of5-amino-2-chloro-pyridine (III-1) as the Boc derivative, followed bydirected lithiation and iodine quench, followed by acid mediateddeprotection to afford the iodo-derivative (III-2) (see Cooper et al.Bioorg. Med. Chem. Lett. 2001, 11, 1233). The pyrrolo-pyridine (III-3)is then formed through base mediated enamine formation and ring closureof the iodo-derivative (III-2) (see Sablayrolles et. al. Bull. Chim.Soc. Fr. 1989, 4, 467). Alkylation of the pyrrolo-pyridine nitrogen videsupra affords (III-4) amenable to metal mediated cross coupling at thechloride moiety or thermal displacement with a suitable alcohol and baseunder standard conditions yielding compounds of Formula (III-5).

A further non-limiting example of a synthetic approach toward compoundsof Formula (C) is shown as reaction Scheme IV, also in FIG. 3. Thecommercially available 5-amino-2-methoxypyridine (IV-1) can bederivatized to the disubstituted anilide (IV-2) by either reductiveamination with an aldehyde and a suitable reducing agent, for examplesodium cyanoborohydride, a procedure well documented in the art, or baseinduced alkylation with a suitable alkylating agent in an appropriatesolvent such as DMF. Conversion of (IV-2) to the hydrazide (IV-3) isachieved under standard conditions. Subsequent heating with a suitablesubstituted ketone under acid catalysis to induce a Fischer indolizationthen furnishes (IV-4), thereby creating the pyrrolo-pyridine framework.Removal of the methyl group under conditions described previously inScheme II yields the intermediate alcohol (IV-5). SubsequentO-alkylation mediated by silver(I) salts and an appropriate electrophileyields compounds having the structure of Formula (IV-6). Alternatively,the intermediate alcohol (IV-5) may be converted to the chloride (III-4)to allow the introduction of the R₁ group, via metal mediated coupling,as described above.

A non-limiting example of a synthetic approach toward compounds ofFormula (D) is shown as Scheme V in FIG. 4. Preparation of thepyrrolo-pyridine derivatives is accomplished in a similar manner asScheme III. Starting with 5-amino-2-chloro-pyridine (III-1) theintroduction of the iodide functionality at the 5-position isaccomplished using iodine and a silver(II) salt (see Cooper et. al.Bioorg. Med Chem. Lett. 2001, 11, 1233) gives the tri-substitutedpyridine (V-1). The pyrrolo-pyridine (V-2) is then formed through basemediated enamine formation and ring closure of the iodo-derivative (V-1)(see Sablayrolles et. al. Bull. Chim. Soc. Fr. 1989, 4, 467). Alkylationof the pyrrolo-pyridine nitrogen vide supra affords a chloro-derivativeamenable to metal mediated cross coupling at the chloride moiety, orthermal displacement with a suitable alcohol and base under standardconditions, yielding pyrrolo-pyridines of Formula (V-3), oralternatively the introduction of the R₁ group, via metal mediatedcoupling, yields pyrrolo-pyridines of Formula (V-4).

Another non-limiting synthetic approach toward compounds of Formula (C)and compounds of Formula (D) is described in Scheme VI of FIG. 4. Suchcompounds may be prepared by forming the pyrrolo-pyridine framework(VI-2) from the iodo-derivative (VI-1) through palladium mediatedcoupling of a terminal alkyne (see Cooper et. al. Bioorg. Med. Chem.Lett. 2001, 11, 1233). The pyrrolo-pyridine (VI-2) may then be treatedas shown in Scheme III, wherein the pyrrolo-pyridine (VI-2) undergoesN-alkylation with a variety of substituted alkyl halides, mesylates ortosylates, and the like, followed by methoxylation to yield compounds ofFormula (VI-5), which can be further acylated with an appropriateacylating agent and aluminum chloride to yield compounds of Formula(VI-8). Alternatively, the pyrrolo-pyridine (VI-2) may undergointroduction of substituents at the 3-position (VI-3), by way of examplethio substituents through reaction with a disulfide and appropriate baseand solvent (see Atkinson, Hamel and Girard, Synthesis, 1988, 480 andreferences cited therein). Compounds of Formula (VI-3) may then betreated as shown in Scheme III, wherein the pyrrolo-pyridine (VI-3) maythen be N-alkylated with a variety of substituted alkyl halides,mesylates or tosylates, and the like, followed by methoxylation to yieldcompounds of Formula (VI-6). In addition, the pyrrolo-pyridine (VI-2)may undergo acylation to yield the acyl derivatives (VI-4) ((see Prasitet. al. U.S. Pat. No. 5,204,344), followed by alkylation usingconditions described by Dillard et. al. (J. Med. Chem. 1996, 39, 5119),or as shown in Scheme III, to yield the substituted pyrrolo-pyridines(VI-7).

A non-limiting example of a synthetic approach toward pyrazinecontaining compounds of Formula (E) is shown as Scheme VII in FIG. 5.Preparation of 3,5-dibromo-pyrazin-2-yl amine (VII-2) is accomplishedthrough bromination of 2-aminopyrazine (VII-1) with NBS (see Jiang et.al. Bioorg. Med. Chem. Lett. 2001, 9, 1149). Reaction of the dibromidewith an appropriately substituted ketone under basic conditions videsupra affords the pyrrolo-pyrazine core (VII-3). N-alkylation of thepyrrolo-pyrazine nitrogen under standard conditions (cf Scheme I) andtransformation of the aryl bromide (VII-4) to the alkoxy derivatizedpyrrolo-pyrazine (VII-5) may be carried out with either metal mediatedcatalysis or thermolysis with the desired alcohol. The aryl bromide(VII-4) may also be converted to the (VII-6) via metal mediated couplingas described above.

A non-limiting example of a synthetic approach toward pyrimidinecontaining compounds of Formula (F) is shown as Scheme VIII, also inFIG. 5. Starting with the known 2-bromo-5-amino-pyrimidine (VIII-1) (seeKrchnak et. al. Collect. Czech. Chem. Commun. 1975, 40, 1396), the aminofunctionality is Boc protected (VIII-2). Ortho-lithiation and iodinationunder standard conditions of the Boc-protected derivative (VIII-2)affords the iodo-pyrimidine (VIII-3). Treatment of this compound underbasic conditions with an appropriately functionalized ketone vide suprayields the desired pyrrolo-pyrimidine core (VIII-4). Thepyrrolo-pyrimidine (VIII-4) may then undergo N-alkylation with a varietyof substituted alkyl halides, mesylates or tosylates, and the like, togive (VIII-5), followed by alkoxylation to yield compounds of Formula(VIII-6). The aryl bromide (VIII-5) may also be converted to the(VIII-7) via metal mediated coupling as described above.

A non-limiting example of a synthetic approach toward pyridazinescontaining compounds of Formula (G) is shown as Scheme IX, in FIG. 6.Such compounds may be prepared from commercially available3,6-dichloropyridazine (IX-1) through conversion to the amino derivative(IX-2) (Hauser et. al. J. Org. Chem. 1984, 49, 2240). Introduction ofiodine at the 4-position is achieved through the N-Boc directedortho-lithiation and iodine quench vide supra, to yield pyridazine(IX-3). Condensation of the pyridazine (IX-3) with a substituted ketoneunder basic conditions provides the pyrrolo-pyridazine core (IX-4). Thepyrrolo-pyridazine (IX-4) may then undergo N-alkylation with a varietyof substituted alkyl halides, mesylates or tosylates, and the like, togive (IX-5), followed by alkoxylation to yield compounds of Formula(IX-6).

Alternatively, a non-limiting example of a synthetic approach towardpyridazines containing compounds of Formula (G) is shown as Scheme X, inFIG. 6. Pyridazines may also be obtained through the synthesis asoutlined in Scheme X (see Bourette et. al. Synlett 2003, 10, 1482).Sequential reaction of 1,1-bis(thiomethyl)-2-nitroethylene with asuitably substituted benzylic amine followed by reaction with hydrazineaffords the intermediate (X-1). Pyridazine (X-2) formation throughreaction with methyl dimethoxyacetate and reaction of the resultingnitro-pyridazine with HBr in AcOH furnishes the bromide (X-3). The corepyrrolo-pyridazine (X-4) is then constructed as before vide suprathrough reaction with a suitably substituted ketone. Deprotection of themethoxy group to afford the alcohol (X-5) allows either directconversion to the desired scaffold (X-6) through alkylation understandard conditions or conversion to the pyridizinyl chloride (X-7) andsubsequent nucleophilic displacement with an appropriate alcohol.Installation of alternative substitutents R₁ may also be accomplishedthrough metal mediated reaction of the pyridizinyl chloride (X-7) withan appropriate reagent to afford (X-8).

Synthesis of Fused-Pyrrolo Scaffolds for Compounds of Formula (A)

Additional non-limiting examples of the synthetic strategy towardfused-pyrrolo scaffold for compounds of Formula (A) include the varioussyntheses of shown in schemes A-W in FIGS. 7-11. For illustrativepurposes, the initial starting material used throughout these syntheticschemes is an optionally substituted pyridine, which yields optionallysubstituted pyrrolo-pyridines. However, the initial starting materialfor such syntheses may also include optionally substituted pyrazines togive optionally substituted pyrrolo-pyrazine, optionally substitutedpyrimidines to give optionally substituted pyrrolo-pyrimidine, oroptionally substituted pyridazines to give optionally substitutedpyrrolo-pyridazines.

Further Forms of Compounds

For convenience, the form and other characteristics of the compoundsdescribed in this section and other parts herein use a single formula,such as “Formula (A),” by way of example. In addition, the form andother characteristics of the compounds described herein apply equallywell to all formulas presented herein that fall within the scope ofFormula (A). For example, the pharmaceutical compositions andformulations described herein can be applied to compounds having thestructure of Formula (B), Formula (C), Formula (D), Formula (E), Formula(F), Formula (G), Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), Formula (VII) Formula (VIII), Formula(IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula(XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII),Formula (XIX), Formula (XX), Formula (XXI), Formula (XXII), Formula(XXIII) and Formula (XXIV), as well as to all of the specific compoundsthat fall within the scope of these generic formulae.

Compounds of Formula (A) can be prepared as a pharmaceuticallyacceptable acid addition salt (which is a type of a pharmaceuticallyacceptable salt) by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, including, butnot limited to, inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid,and the like; and organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroaceticacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnaric acid, mandelic acid, arylsulfonic acid, methanesulfonic acid,ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-Carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

Alternatively, compounds of Formula (A) can be prepared as apharmaceutically acceptable base addition salts (which is a type of apharmaceutically acceptable salt) by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base,including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like and inorganic bases such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like.

Compounds of Formula (A) can be prepared as a pharmaceuticallyacceptable salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, for example an alkali metalion, an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base. In addition, the salt forms of the disclosed compounds canbe prepared using salts of the starting materials or intermediates.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds of Formula (A) can beconveniently prepared or formed during the processes described herein.By way of example only, hydrates of compounds of Formula (A) can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents including, but not limited to,dioxane, tetrahydrofuran or methanol. In addition, the compoundsprovided herein can exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

Compounds of Formula (A) may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds of Formula (A) include crystalline forms, also knownas polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

Compounds of Formula (A) in unoxidized form can be prepared fromN-oxides of compounds of Formula (A) by treating with a reducing agent,such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorustrichloride, tribromide, or the like in a suitable inert organicsolvent, such as, but not limited to, acetonitrile, ethanol, aqueousdioxane, or the like at 0 to 80° C.

Compounds of Formula (A) can be prepared as prodrugs. Prodrugs aregenerally drug precursors that, following administration to a subjectand subsequent absorption, are converted to an active, or a more activespecies via some process, such as conversion by a metabolic pathway.Some prodrugs have a chemical group present on the prodrug that rendersit less active and/or confers solubility or some other property to thedrug. Once the chemical group has been cleaved and/or modified from theprodrug the active drug is generated. Prodrugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. The prodrug may also have improved solubilityin pharmaceutical compositions over the parent drug.

Prodrugs may be designed as reversible drug derivatives, for use asmodifiers to enhance drug transport to site-specific tissues. The designof prodrugs to date has been to increase the effective water solubilityof the therapeutic compound for targeting to regions where water is theprincipal solvent. See, e.g., Fedorak et al., Am. J. Physiol.,269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994);Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H.Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int.J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein in theirentirety.

Additionally, prodrug derivatives of compounds of Formula (A) can beprepared by methods known to those of ordinary skill in the art (e.g.,for further details see Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985). By way of example only,appropriate prodrugs can be prepared by reacting a non-derivatizedcompound of Formula (A) with a suitable carbamylating agent, such as,but not limited to, 1,1-acyloxyalkylcarbanochloridate, para-nitrophenylcarbonate, or the like. Prodrug forms of the herein described compounds,wherein the prodrug is metabolized in vivo to produce a derivative asset forth herein are included within the scope of the claims. Indeed,some of the herein-described compounds may be a prodrug for anotherderivative or active compound.

Sites on the aromatic ring portion of compounds of Formula (A) can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. The compounds of Formula (A) may possess oneor more stereocenters and each center may exist in the R or Sconfiguration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof Compounds of Formula (A) can be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of the compoundsdescribed herein, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.

Additionally, the compounds and methods provided herein may exist asgeometric isomers. The compounds and methods provided herein include allcis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well asthe appropriate mixtures thereof. In some situations, compounds mayexist as tautomers. All tautomers are included within the formulasdescribed herein are provided by compounds and methods herein. Inadditional embodiments of the compounds and methods provided herein,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion may also be useful forthe applications described herein.

Routes of Administration

For convenience, the routes of administration described in this sectionand other parts herein use a single formula, such as “Formula (A),” byway of example. In addition, the routes of administration describedherein apply equally well to all formulas presented herein that fallwithin the scope of Formula (A), For example, the pharmaceuticalcompositions and formulations described herein can be applied tocompounds having the structure of Formula (B), Formula (C), Formula (D),Formula (E), Formula (F), Formula (G), Formula (I), Formula (II),Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII)Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII),Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula(XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI),Formula (XXII), Formula (XXIII) and Formula (XXIV), as well as to all ofthe specific compounds that fall within the scope of these genericformulae.

Suitable routes of administration include, but are not limited to,intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

Alternately, one may administer the compound in a local rather thansystemic manner, for example, via injection of the compound directlyinto an organ, often in a depot preparation or sustained releaseformulation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Furthermore, one may administer the drug in atargeted drug delivery system, for example, in a liposome coated withorgan-specific antibody. The liposomes will be targeted to and taken upselectively by the organ. In addition, the drug may be provided in theform of a rapid release formulation, in the form of an extended releaseformulation, or in the form of an intermediate release formulation.

Pharmaceutical Composition/Formulation

For convenience, the pharmaceutical compositions and formulationsdescribed in this section and other parts herein use a single formula,such as “Formula (A),” by way of example. In addition, thepharmaceutical compositions and formulations described herein applyequally well to all formulas presented herein that fall within the scopeof Formula (A). For example, the pharmaceutical compositions andformulations described herein can be applied to compounds having thestructure of Formula (B), Formula (C), Formula (D), Formula (E), Formula(F), Formula (G), Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), Formula (VII) Formula (VIII), Formula(IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula(XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII),Formula (XIX), Formula (XX), Formula (XXI), Formula (XXII), Formula(XXIII) and Formula (XXIV), as well as to all of the specific compoundsthat fall within the scope of these generic formulae.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

Provided herein are pharmaceutical compositions comprising a compound ofFormula (A) and a pharmaceutically acceptable diluent(s), excipient(s),or carrier(s). In addition, the compounds described herein can beadministered as pharmaceutical compositions in which compounds ofFormula (A) are mixed with other active ingredients, as in combinationtherapy.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (A) with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. The pharmaceutical compositionfacilitates administration of the compound to an organism. In practicingthe methods of treatment or use provided herein, therapeuticallyeffective amounts of compounds of Formula (A) provided herein areadministered in a pharmaceutical composition to a mammal having adisease or condition to be treated. Preferably, the mammal is a human. Atherapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures.

For intravenous injections, compounds of Formula (A) may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

For oral administration, compounds of Formula (A) can be formulatedreadily by combining the active compounds with pharmaceuticallyacceptable carriers or excipients well known in the art. Such carriersenable the compounds described herein to be formulated as tablets,powders, pills, dragees, capsules, liquids, gels, syrups, elixirs,slurries, suspensions and the like, for oral ingestion by a patient tobe treated.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as: for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in a conventional manner.Parental injections may involve bolus injection or continuous infusion.Formulations for injection may be presented in unit dosage form, e.g.,in ampoules or in multi-dose containers, with an added preservative. Thepharmaceutical composition of Formula (A) may be in a form suitable forparenteral injection as a sterile suspensions, solutions or emulsions inoily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. Additionally, suspensions ofthe active compounds may be prepared as appropriate oily injectionsuspensions. Suitable lipophilic solvents or vehicles include fatty oilssuch as sesame oil, or synthetic fatty acid esters, such as ethyl oleateor triglycerides, or liposomes. Aqueous injection suspensions maycontain substances which increase the viscosity of the suspension, suchas sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents whichincrease the solubility of the compounds to allow for the preparation ofhighly concentrated solutions. Alternatively, the active ingredient maybe in powder form for constitution with a suitable vehicle, e.g.,sterile pyrogen-free water, before use.

The compounds of Formula (A) can be administered topically and can beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compounds can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

Formulations suitable for transdermal administration of compounds havingthe structure of Formula (A) may employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. Such patches may be constructed for continuous, pulsatile,or on demand delivery of pharmaceutical agents. Still further,transdermal delivery of the compounds of Formula (A) can be accomplishedby means of iontophoretic patches and the like. Additionally,transdermal patches can provide controlled delivery of the compoundsFormula (A). The rate of absorption can be slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. Conversely, absorption enhancers can be used to increaseabsorption. An absorption enhancer or carrier can include absorbablepharmaceutically acceptable solvents to assist passage through the skin.For example, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

For administration by inhalation, the compounds of Formula (A) maybe ina form as an aerosol, a mist or a powder. Pharmaceutical compositions ofFormula (A) are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound and a suitable powder base such as lactose orstarch.

The compounds of Formula (A) may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Pharmaceutical compositions may be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. Pharmaceutical compositionscomprising a compound of Formula (A) may be manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions will include at least onepharmaceutically acceptable carrier, diluent or excipient and a compoundof Formula (A) described herein as an active ingredient in free-acid orfree-base form, or in a pharmaceutically acceptable salt form. Inaddition, the methods and pharmaceutical compositions described hereininclude the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. Additionally, the compounds described herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.In addition, the pharmaceutical compositions may include other medicinalor pharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions can also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The compositions may be inliquid solutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionsmay also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and so forth.

A composition comprising a compound of Formula (A) can illustrativelytake the form of a liquid where the agents are present in solution, insuspension or both. Typically when the composition is administered as asolution or suspension a first portion of the agent is present insolution and a second portion of the agent is present in particulateform, in suspension in a liquid matrix. In some embodiments, a liquidcomposition may include a gel formulation. In other embodiments, theliquid composition is aqueous.

Useful aqueous suspension can also contain one or more polymers assuspending agents. Useful polymers include water-soluble polymers suchas cellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Useful compositions can also comprise an mucoadhesive polymer,selected for example from carboxymethylcellulose, carbomer (acrylic acidpolymer), poly(methylmethacrylate), polyacrylamide, polycarbophil,acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Useful compositions may also include solubilizing agents to aid in thesolubility of a compound of Formula (A). The term “solubilizing agent”generally includes agents that result in formation of a micellarsolution or a true solution of the agent. Certain acceptable nonionicsurfactants, for example polysorbate 80, can be useful as solubilizingagents, as can ophthalmically acceptable glycols, polyglycols, e.g.,polyethylene glycol 400, and glycol ethers.

Useful compositions may also include one or more pH adjusting agents orbuffering agents, including acids such as acetic, boric, citric, lactic,phosphoric and hydrochloric acids; bases such as sodium hydroxide,sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodiumlactate and tris-hydroxymethylaminomethane; and buffers such ascitrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids,bases and buffers are included in an amount required to maintain pH ofthe composition in an acceptable range.

Useful compositions may also include one or more salts in an amountrequired to bring osmolality of the composition into an acceptablerange. Such salts include those having sodium, potassium or ammoniumcations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful compositions may also include one or more preservatives toinhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Still other useful compositions may include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

Aqueous suspension compositions can be packaged in single-dosenon-reclosable containers. Alternatively, multiple-dose reclosablecontainers can be used, in which case it is typical to include apreservative in the composition.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles Or carriers for hydrophobic drugs. Certainorganic solvents such as N-methylpyrrolidone also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

All of the formulations described herein may benefit from antioxidants,metal chelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

Methods of Dosing and Treatment Regimens

For convenience, the administration methods of dosing and treatmentregimens described in this section and other parts herein use a singleformula, such as “Formula (A),” by way of example. In addition, theadministration methods and treatment methods described herein applyequally well to all formulas, or combinations or mixtures of formulas,presented herein that fall within the scope of Formula (A), includingcompounds having the structure of Formula (B), Formula (C), Formula (D),Formula (E), Formula (F), Formula (G), Formula (I), Formula (II),Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII)Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII),Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula(XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI),Formula (XXII), Formula (XXIII) and Formula (XXIV), as well as to all ofthe specific compounds that fall within the scope of these genericformulae.

The compounds of Formula (A) can be used in the preparation ofmedicaments for the treatment of leukotriene-dependent or leukotrienemediated diseases or conditions. In addition, a method for treating anyof the diseases or conditions described herein in a subject in need ofsuch treatment, involves administration of pharmaceutical compositionscontaining at least one compound of Formula (A), or a pharmaceuticallyacceptable salt, pharmaceutically acceptable N-oxide, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or conditionsprevious therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days,and 365 days. The dose reduction during a drug holiday may be from10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

Once improvement of the patients conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dosemay conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds of Formula (A) describedherein are from about 0.01 to 2.5 mg/kg per body weight. An indicateddaily dosage in the larger mammal, including, but not limited to,humans, is in the range from about 0.5 mg to about 100 mg, convenientlyadministered in divided doses, including, but not limited to, up to fourtimes a day or in extended release form. Suitable unit dosage forms fororal administration comprise from about 1 to 50 mg active ingredient.The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Use of FLAP Modulators to Prevent and/or Treat Leukotriene-Dependent orLeukotriene Mediated Diseases or Conditions

For convenience, the use of FLAP modulators to prevent and/or treatleukotriene-dependent or leukotriene mediated (or leukotriene-related)diseases or conditions described in this section and other parts hereinuse a single formula, such as “Formula (A),” by way of example. Inaddition, the administration methods and treatment methods describedherein apply equally well to all formulas, or combinations or mixturesof formulas, presented herein that fall within the scope of Formula (A),including compounds having the structure of Formula (B), Formula (C),Formula (D), Formula (E), Formula (F), Formula (G), Formula (I), Formula(II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula(VII) Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula(XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI),Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula(XXI), Formula (XXII), Formula (XXIII) and Formula (XXIV), as well as toall of the specific compounds that fall within the scope of thesegeneric formulae.

The therapy of leukotriene-dependent or leukotriene mediated diseases orconditions is designed to modulate the activity of FLAP. Such modulationmay include, by way of example only, inhibiting or antagonizing FLAPactivity. For example, a FLAP inhibitor can be administered in order todecrease synthesis of leukotrienes within the individual, or possibly todownregulate or decrease the expression or availability of the FLAP mRNAor specific splicing variants of the FLAP mRNA. Downregulation ordecreasing expression or availability of a native FLAP mRNA or of aparticular splicing variant could minimize the expression or activity ofa defective nucleic acid or the particular splicing variant and therebyminimize the impact of the defective nucleic acid or the particularsplicing variant.

In accordance with one aspect, compositions and methods described hereininclude compositions and methods for treating, preventing, reversing,halting or slowing the progression of leukotriene-dependent orleukotriene mediated diseases or conditions once it becomes clinicallyevident, or treating the symptoms associated with or related toleukotriene-dependent or leukotriene mediated diseases or conditions, byadministering to the subject a compound of Formula (A) or pharmaceuticalcomposition or medicament which includes a compound of Formula (A). Thesubject may already have a leukotriene-dependent or leukotriene mediateddisease or condition at the time of administration, or be at risk ofdeveloping a leukotriene-dependent or leukotriene mediated disease orcondition. The symptoms of leukotriene-dependent or leukotriene mediateddiseases or conditions in a subject can be determined by one skilled inthe art and are described in standard textbooks.

The activity of 5-lipoxygenase activating protein in a mammal may bedirectly or indirectly modulated by the administration of (at leastonce) an effective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A), to a mammal. Such modulation includes, but is not limitedto, reducing and/or inhibiting the activity of 5-lipoxygenase activatingprotein. In addition, the activity of leukotrienes in a mammal may bedirectly or indirectly modulated, including reducing and/or inhibiting,by the administration of (at least once) an effective amount of at leastone compound of Formula (A), or pharmaceutical composition or medicamentwhich includes a compound of Formula (A), to a mammal. Such modulationincludes, but is not limited to, reducing and/or inhibiting the activityof 5-lipoxygenase activating protein.

Prevention and/or treatment leukotriene-dependent or leukotrienemediated diseases or conditions may comprise administering to a mammalat least once an effective amount of at least one compound of Formula(A), or pharmaceutical composition or medicament which includes acompound of Formula (A). By way of example, the prevention and/ortreatment of inflammation diseases or conditions may compriseadministering to a mammal at least once an effective amount of at leastone compound of Formula (A), or pharmaceutical composition or medicamentwhich includes a compound of Formula (A). Leukotriene-dependent orleukotriene mediated diseases or conditions that may be treated by amethod comprising administering to a mammal at least once an effectiveamount of at least one compound of Formula (A), or pharmaceuticalcomposition or medicament which includes a compound of Formula (A),include, but are not limited to, bone diseases and disorder,cardiovascular diseases and disorders, inflammatory diseases anddisorders, dermatological diseases and disorders, ocular diseases anddisorders, cancer and other proliferative diseases and disorders,respiratory diseases and disorder, and non-cancerous disorders.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound of Formula (A), or pharmaceutical compositionor medicament which includes a compound of Formula (A). By way ofexample the respiratory disease may be asthma; see Riccioni et al, Ann.Clin. Lab. Sci., v34, 379-387 (2004). In addition, the respiratorydisease may include, but is not limited to, adult respiratory distresssyndrome and allergic (extrinsic) asthma, non-allergic (intrinsic)asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnalasthma, allergen-induced asthma, aspirin-sensitive asthma,exercise-induced asthma, isocapnic hyperventilation, child-onset asthma,adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, allergic rhinitis, vascularresponses, endotoxin shock, fibrogenesis, pulmonary fibrosis, allergicdiseases, chronic inflammation, and adult respiratory distress syndrome.

By way of example only, included in such treatment methods are methodsfor preventing chronic obstructive pulmonary disease comprisingadministering to the mammal at least once an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A). In addition,chronic obstructive pulmonary disease includes, but is not limited to,chronic bronchitis or emphysema, pulmonary hypertension, interstitiallung fibrosis and/or airway inflammation and cystic fibrosis.

By way of example only, included in such treatment methods are methodsfor preventing increased mucosal secretion and/or edema in a disease orcondition comprising administering to the mammal at least once aneffective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A); see Jala et al,Trends in Immunol., v25, 315-322 (2004) and mehrabian et al, Curr. Opin.Lipidol., v14, 447-457 (2003).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing cardiac reperfusion injuryfollowing myocardial ischemia and/or endotoxic shock comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for reducing the constriction of bloodvessels in a mammal comprising administering at least once to the mammalan effective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for lowering or preventing an increase inblood pressure of a mammal comprising administering at least once to themammal an effective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing eosinophil and/or basophiland/or dendritic cell and/or neutrophil and/or monocyte recruitmentcomprising administering at least once to the mammal an effective amountof at least one compound of Formula (A), or pharmaceutical compositionor medicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment of abnormalbone remodeling, loss or gain, including diseases or conditions as, byway of example, osteopenia, osteoporosis, Paget's disease, cancer andother diseases comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing ocular inflammation andallergic conjunctivitis, vernal keratoconjunctivitis, and papillaryconjunctivitis comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A); see Lambiase et al, Arch. Opthalmol., v121, 615-620 (2003).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing CNS disorders comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A). CNS disordersinclude, but are not limited to, multiple sclerosis, Parkinson'sdisease, Alzheimer's disease, stroke, cerebral ischemia, retinalischemia, post-surgical cognitive dysfunction, migraine, peripheralneuropathy/neuropathic pain, spinal cord injury, cerebral edema and headinjury.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cancer comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A). The type of cancermay include, but is not limited to, pancreatic cancer and other solid orhematological tumors, see Poff and Balazy, Curr. Drug Targets Inflamm.Allergy, v3, 19-33 (2004) and Steele et al, Cancer Epidemiology &Prevention, v8, 467-483 (1999).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing endotoxic shock and septicshock comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (A), or pharmaceuticalcomposition or medicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein methods for preventing rheumatoid arthritis andosteoarthritis comprising administering at least once to the mammal aneffective amount of at least one compound of Formula (A), orpharmaceutical composition or medicament which includes a compound ofFormula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for preventing increased GI diseasescomprising administering at least once to the mammal an effective amountof at least one compound of Formula (A), or pharmaceutical compositionor medicament which includes a compound of Formula (A). Such GI diseasesinclude, by way of example only, inflammatory bowel disease (IBD),colitis and Crohn's disease.

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the reduction of inflammation whilealso preventing transplant rejection or preventing or treating tumors oracclerating the healing of wounds comprising administering at least onceto the mammal an effective amount of at least one compound of Formula(A), or pharmaceutical composition or medicament which includes acompound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the prevention or treatment ofrejection or dysfunction in a transplanted organ or tissue comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating type II diabetes comprisingadministering to at least once to the mammal an effective amount of atleast one compound of Formula (A), or pharmaceutical composition ormedicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for treating inflammatory responses of theskin comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (A), or pharmaceuticalcomposition or medicament which includes a compound of Formula (A). Suchinflammatory responses of the skin include, by way of example,psoriasis, dermatitis, contact dermatitis, eczema, urticaria, rosacea,wound healing and scarring. In another aspect are methods for reducingpsoriatic lesions in the skin, joints, or other tissues or organs,comprising administering at least once to the mammal an effective amountof at least one compound of Formula (A), or pharmaceutical compositionor medicament which includes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of cystitis, including,by way of example only, interstitial cystitis, comprising administeringat least once to the mammal an effective amount of at least one compoundof Formula (A), or pharmaceutical composition or medicament whichincludes a compound of Formula (A).

By way of example only, included in the prevention/treatment methodsdescribed herein are methods for the treatment of metabolic syndromessuch as Familial Mediterranean Fever comprising administering at leastonce to the mammal an effective amount of at least one compound ofFormula (A), or pharmaceutical composition or medicament which includesa compound of Formula (A).

Combination Treatments

For convenience, the combination treatments described in this sectionand other parts herein use a single formula, such as “Formula (A),” byway of example. In addition, the combination treatments described hereinapply equally well to all formulas presented herein that fall within thescope of Formula (A). For example, the pharmaceutical compositions andformulations described herein can be applied to compounds having thestructure of Formula (B), Formula (C), Formula (D), Formula (E), Formula(F), Formula (G), Formula (I), Formula (II), Formula (III), Formula(IV), Formula (V), Formula (VI), Formula (VII) Formula (VIII), Formula(IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula(XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII),Formula (XIX), Formula (XX), Formula (XXI), Formula (XXII), Formula(XXIII) and Formula (XXIV), as well as to all of the specific compoundsthat fall within the scope of these generic formulae.

In certain instances, it may be appropriate to administer at least onecompound of Formula (A) in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein is inflammation, thenit may be appropriate to administer an anti-inflammatory agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may have minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, by way of example only, the benefit ofexperienced by a patient may be increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Byway of example only, in a treatment for asthma involving administrationof one of the compounds described herein, increased therapeutic benefitmay result by also providing the patient with other therapeutic agentsor therapies for asthma. In any case, regardless of the disease,disorder or condition-being treated, the overall benefit experienced bythe patient may simply be additive of the two therapeutic agents or thepatient may experience a synergistic benefit.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literature. Acombination treatment regimen may encompasses treatment regimens inwhich administration of a FLAP or 5-LO inhibitor described herein isinitiated prior to, during, or after treatment with a second agentdescribed above, and continues until any time during treatment with thesecond agent or after termination of treatment with the second agent. Italso includes treatments in which a FLAP or 5-LO inhibitor describedherein and the second agent being used in combination are administeredsimultaneously or at different times and/or at decreasing or increasingintervals during the treatment period. Combination treatment furtherincludes periodic treatments that start and stop at various times toassist with the clinical management of the patient. For example, a FLAPor 5-LO inhibitor described herein in the combination treatment can beadministered weekly at the onset of treatment, decreasing to biweekly,and decreasing further as appropriate.

Compositions and methods for combination therapy are provided herein. Inaccordance with one aspect, the pharmaceutical compositions disclosedherein are used to treat leukotriene-dependent or leukotriene mediatedconditions. In accordance with another aspect, the pharmaceuticalcompositions disclosed herein are used to treat respiratory diseases,where treatment with a FLAP inhibitor is indicated, in particularasthma, and to induce bronchodilation in a subject. In one embodiment,pharmaceutical compositions disclosed herein are used to treat a subjectsuffering from a vascular inflammation-driven disorder. In oneembodiment, the pharmaceutical compositions disclosed herein are used totreat a subject susceptible to myocardial infarction (MI).

Combination therapies described herein can be used as part of a specifictreatment regimen intended to provide a beneficial effect from theco-action of a FLAP inhibitors described herein and a concurrenttreatment. It is understood that the dosage regimen to treat, prevent,or ameliorate the condition(s) for which relief is sought, can bemodified in accordance with a variety of factors. These factors includethe type of respiratory disorder and the type of bronchodilation fromwhich the subject suffers, as well as the age, weight, sex, diet, andmedical condition of the subject. Thus, the dosage regimen actuallyemployed can vary widely and therefore can deviate from the dosageregimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is one of thecompounds described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

In addition, the compounds of Formula (A) may also be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of Formula (A) and /orcombinations with other therapeutics are combined with genetic testingto determine whether that individual is a carrier of a mutant gene thatis known to be correlated with certain diseases or conditions.

The compounds of Formula (A) and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms,preferably within the first 48 hours of the onset of the symptoms, morepreferably within the first 6 hours of the onset of the symptoms, andmost preferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over 5 minutes toabout 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. The length of treatment can vary for eachsubject, and the length can be determined using the known criteria. Forexample, the compound or a formulation containing the compound can beadministered for at least 2 weeks, preferably about 1 month to about 5years, and more preferably from about 1 month to about 3 years.

By way of example, therapies which combine compounds of Formula (A) withinhibitors of leukotriene synthesis or leukotriene receptor antagonists,either acting at the same or other points in the leukotriene synthesispathway, could prove to be particularly useful for treatingleukotriene-dependent or leukotriene mediated diseases or conditions. Inaddition, by way of example, therapies which combine compounds offormula (A) with inhibitors of inflammation could prove to beparticularly useful for treating leukotriene-dependent or leukotrienemediated diseases or conditions.

Anti-Inflammatory Agents

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with ananti-inflammatory agent including, but not limited to, arthrotec,asacol, auralglan, azulfidine, daypro, etodolac, ponstan, salofalk, andsolumedrol; non-steroidal anti-inflammatory agents, byway of example,aspirin (Bayer™, Bufferin™), indomethacin (Indocin™), rofecoxib(Vioxx™), celecoxib (Celebrex™), valdecoxib (Bextra™), diclofenac,etodolac, ketoprofen, lodine, mobic, nabumetone, naproxen, piroxicam;and corticosteroids, by way of example, celestone, prednisone, anddeltasone. Corticosteroids do not directly inhibit leukotrieneproduction, therefore co-dosing with steroids could provide additionalanti-inflammatory benefit.

By way of example, asthma is a chronic inflammatory diseasecharacterized by pulmonary eosinophilia and airway hyperresponsiveness.Zhao et al., Proteomics, Jul. 4, 2005. In patients with asthma,leukotrienes may be released from mast cells, eosinophils, andbasophils. The leukotrienes are involved in contraction of airway smoothmuscle, an increase in vascular permeability and mucus secretions, andhave been reported to attract and activate inflammatory cells in theairways of asthmatics (Siegel et al., ed., Basic Neurochemistry,Molecular, Cellular and Medical Aspects, Sixth Ed., Lippincott Williams& Wilkins, 1999). Thus, in another embodiment described herein, themethods for treatment of respiratory diseases includes administration toa patient compounds, pharmaceutical compositions, or medicamentsdescribed herein in combination with an anti-inflammatory agent.

Leukotriene Receptor Antagonists

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination withleukotriene receptor antagonists including, but are not limited to,CysLT₁/CysLT₂ dual receptor antagonists and CysLT₁ receptoranatagonists. In another embodiment described herein, methods fortreatment of leukotriene-dependent or leukotriene mediated conditions ordiseases includes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with aCysLT₁/CysLT₂ dual receptor antagonist. CysLT₁/CysLT₂ dual receptorantagonists include, but are not limited to, BAY u9773, Cuthbert et alEP 00791576 (published 27 Aug. 1997), DUO-LT (Galczenski et al, D38,Poster F4 presented at American Thoracic Society, May 2002) and Tsuji etal, Org. Biomol. Chem., 1, 3139-3141, 2003. For a particular patient,the most appropriate formulation or method of use of such combinationtreatments may depend on the type of leukotriene-dependent orleukotriene mediated disorder, the time period in which the FLAPinhibitor acts to treat the disorder and the time period in which theCysLT₁/CysLT₂ dual receptor antagonist acts to inhibit CysLT receptoractivity. By way of example only, such combination treatments may beused for treating a patient suffering from a respiratory disorders.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseasesincludes administered to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with aCysLT₁ receptor antagonist. CysLT₁ receptor antagonists include, but arenot limited to, Zafirlukast (“Accolate™”), Montelukast (“Singulair™”),Prankulast (“Onon™”), and derivatives or analogs thereof. Suchcombinations may be used to treat leukotriene-dependent or leukotrienemediated disorder, including respiratory disorders.

The co-administration of a FLAP or 5-LO inhibitor described herein witha CysLT₁ receptor antagonist or a dual CysLT₁/CysLT₂ receptor antagonistmay have therapeutic benefit over and above the benefit derived from theadministration of a either a FLAP or 5-LO inhibitor or a CysLT₁Rantagonist alone. In the case that substantial inhibition of leukotrieneproduction has undesired effects, partial inhibition of this pathwaythrough the amelioration of the effects of the proinflammatory LTB₄ andcysteinyl leukotrienes combined with the block of the CysLT₁ receptorand/or dual CysLT₁/CysLT₂ receptor block may afford substantialtherapeutic benefits, particularly for respiratory diseases.

Other Combination Therapies

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as proliferative disorders, including cancer, comprisesadministration to a patient compounds, pharmaceutical compositions, ormedicaments described herein in combination with at least one additionalagent selected from the group consisting of alemtuzumab, arsenictrioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab,platinum-based compounds such as cisplatin, cladribine,daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine,5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel™, taxol,temozolomide, thioguanine, or classes of drugs including hormones (anantiestrogen, an antiandrogen, or gonadotropin releasing hormoneanalogues, interferons such as alpha interferon, nitrogen mustards suchas busulfan or melphalan or mechlorethamine, retinoids such astretinoin, topoisomerase inhibitors such as irinotecan or topotecan,tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents totreat signs or symptoms induced by such therapy including allopurinol,filgrastim, granisetron/ondansetron/palonosetron, dronabinol.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of transplanted organs or tissues or cells,comprises administration to a patient compounds, pharmaceuticalcompositions, or medicaments described herein in combination with atleast one additional agent selected from the group consisting ofazathioprine, a corticosteroid, cyclophosphamide, cyclosporin,dacluzimab, mycophenolate mofetil, OKT3, rapamycin, tacrolimus,thymoglobulin.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as atherosclerosis, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from thegroup consisting of HMG-CoA reductase inhibitors (e.g., statins in theirlactonized or dihydroxy open acid forms and pharmaceutically acceptablesalts and esters thereof, including but not limited to lovastatin;simvastatin; dihydroxy open-acid simvastatin, particularly the ammoniumor calcium salts thereof; pravastatin, particularly the sodium saltthereof; fluvastatin, particularly the sodium salt thereof;atorvastatin, particularly the calcium salt thereof; nisvastatin, alsoreferred to as NK-104; rosuvastatin); agents that have bothlipid-altering effects and other pharmaceutical activities; HMG-CoAsynthase inhibitors; cholesterol absorption inhibitors such asezetimibe; cholesterol ester transfer protein (CETP) inhibitors, forexample JTT-705 and CP529, 414; squalene epoxidase inhibitors;squalene-synthetase inhibitors (also known as squalene synthaseinhibitors); acyl-coenzyme A: cholesterol acyltransferase (ACAT)inhibitors including selective inhibitors of ACAT-1 or ACAT-2 as well asdual inhibitors of ACAT-1 and -2; microsomal triglyceride transferprotein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL(low density lipoprotein) receptor inducers; platelet aggregationinhibitors, for example glycoprotein IIb/IIIa fibrinogen receptorantagonists and aspirin; human peroxisome proliferator activatedreceptor gamma (PPARγ) agonists, including the compounds commonlyreferred to as glitazones, for example troglitazone, pioglitazone androsiglitazone and including those compounds included within thestructural class known as thiazolidinediones as well as those PPARγagonists outside the thiazolidinedione structural class; PPARα agonistssuch as clofibrate, fenofibrate including micronized fenofibrate, andgemfibrozil ; PPAR dual α/γ agonists such as5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide,known as KRP-297; vitamin B6 (also known as pyridoxine) and thepharmaceutically acceptable salts thereof such as the HCI salt; vitaminB12 (also known as cyanocobalamin); folic acid or a pharmaceuticallyacceptable salt or ester thereof such as the sodium salt and themethylglucamine salt; anti-oxidant vitamins such as vitamin C and E andbeta carotene; beta-blockers; angiotensin II antagonists such aslosartan; angiotensin converting enzyme inhibitors such as enalapril andcaptopril ; calcium channel blockers such as nifedipine and diltiazam;endothelian antagonists; agents that enhance ABC1 gene expression; FXRand LXR ligands including both inhibitors and agonists; bisphosphonatecompounds such as alendronate sodium; and cyclooxygenase-2 inhibitorssuch as rofecoxib and celecoxib.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of stroke, comprises administration to a patientcompounds, pharmaceutical compositions, or medicaments described hereinin combination with at least one additional agent selected from COX-2inhibitors; nitric oxide synthase inhibitors, such asN-(3-(aminomethyl)benzyl) acetamidine; Rho kinase inhibitors, such asfasudil; angiotension II type-1 receptor antagonists, includingcandesartan, losartan, irbesartan, eprosartan, telmisartan andvalsartan; glycogen synthase kinase 3 inhibitors; sodium or calciumchannel blockers, including crobenetine; p38 MAP kinase inhibitors,including SKB 239063; thromboxane AX-synthetase inhibitors, includingisbogrel, ozagrel, ridogrel and dazoxiben; statins (HMG CoA reductaseinhibitors), including lovastatin, simvastatin, dihydroxy open-acidsimvastatin, pravastatin, fluvastatin, atorvastatin, nisvastatin, androsuvastatin; neuroprotectants, including free radical scavengers,calcium channel blockers, excitatory amino acid antagonists, growthfactors, antioxidants, such as edaravone, vitamin C, TROLOX™, citicolineand minicycline, and reactive astrocyte inhibitors, such as(2R)-2-propyloctanoic acid; beta andrenergic blockers, such aspropranolol, nadolol, timolol, pindolol, labetalol, metoprolol,atenolol, esmolol and acebutolol; NMDA receptor antagonists, includingmemantine; NR2B antagonists, such as traxoprodil; 5-HT1A agonists;receptor platelet fibrinogen receptor antagonists, including tirofibanand lamifiban; thrombin inhibitors; antithrombotics, such as argatroban;antihypertensive agents, such as enalapril; vasodilators, such ascyclandelate; nociceptin antagonists; DPIV antagonists; GABA 5 inverseagonists; and selective androgen receptor modulators.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of pulmonary fibrosis, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected fromanti-inflammatory agents, such as corticosteroids, azathioprine orcyclophosphamide.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of interstitial cystitis, comprises administrationto a patient compounds, pharmaceutical compositions, or medicamentsdescribed herein in combination with at least one additional agentselected from dimethylsulfoxide, omalizumab, and pentosan polysulfate.

In another embodiment described herein, methods for treatment ofleukotriene-dependent or leukotriene mediated conditions or diseases,such as the therapy of disorders of bone, comprises administration to apatient compounds, pharmaceutical compositions, or medicaments describedherein in combination with at least one additional agent selected fromthe group consisting of minerals, vitamins, bisphosphonates, anabolicsteroids, parathyroid hormone or analogs, and cathepsin K inhibitors

Treatment of Leukotriene Based Conditions or Diseases UsingCysLT₁/CysLT₂ Receptor Antagonists

In accordance with another aspect, the compositions and methodsdescribed herein are designed to deliver a CysLT₁/CysLT₂ dual receptorantagonist to block the CysLT receptor activity. The term “CysLTantagonist” or “CysLT receptor antagonist” or “leukotriene receptorantagonist” refers to a therapy that decreases the signaling of CysLTsthrough CysLT receptors. CysLT typically refers to either LTC₄, LTD₄orLTE₄. Cysteinyl leukotrienes are potent smooth muscle constrictingagents, particularly in respiratory and circulatory systems. These aremediated via at least two cell receptors, CysLT₁ and CysLT₂. The CysLT₁receptor and CysLT₂ receptors are G-protein-coupled receptors with sevenputative transmembrane regions and an intracellular domain thatinteracts with G-proteins, Evans et al, Prostaglandins and Other LipidMediators, 68-69, p587-597, (2002). Examples of CysLT₁/CysLT₂ dualreceptor antagonists are BAY u9773, Cuthbert et al EP 00791576(published 27 Aug. 1997), DUO-LT (Galczenski et al, D38, Poster F4presented at American Thoracic Society, May 2002) and Tsuji et al, Org.Biomol. Chem., 1, 3139-3141, 2003.

In certain embodiments, methods for treatment of leukotriene-dependentor leukotriene mediated diseases or conditions includes administering topatients compounds, pharmaceutical compositions, or medicamentscomprising a CysLT₁/CysLT₂ receptor antagonist. By way of example, suchcompounds, pharmaceutical compositions, or medicaments may be used astreatment and/or prevention for respiratory diseases including, but notlimited to, chronic stable asthma.

Diagnostic Methods for Patient Identification

For convenience, the diagnostic and/or patient identification methodsand treatment methods resulting therefrom that are described in thissection and other parts herein use a single formula, such as “Formula(A),” by way of example. In addition, the diagnostic and/or patientidentification methods and treatment methods resulting therefromdescribed herein apply equally well to all formulas, or combinations ormixtures of formulas, presented herein that fall within the scope ofFormula (A), including compounds having the structure of Formula (B),Formula (C), Formula (D), Formula (E), Formula (F), Formula (G), Formula(I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula(VI), Formula (VII) Formula (VIII), Formula (IX), Formula (X), Formula(XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV),Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula(XX), Formula (XXI), Formula (XXII), Formula (XXIII) and Formula (XXIV),as well as to all of the specific compounds that fall within the scopeof these generic formulae.

The screening of “leukotriene-responsive patients” which may be selectedfor treatment with compounds of Formula (A), or pharmaceuticalcompositions or medicaments described herein which include compounds ofFormula (A), or other FLAP modulators, may be accomplished usingtechniques and methods described herein. Such techniques and methodsinclude, by way of example, evaluation of gene haplotypes (genotypeanalysis), monitoring/measurement of biomarkers (phenotype analysis),monitoring/measurement of functional markers (phenotype analysis), whichindicate patient response to known modulators of the leukotrienepathway, or any combination thereof.

Genotype Analysis: FLAP Polymorphisms

Human FLAP has been purified and cloned and is an 18 kilodaltonmembrane-bound protein which is most highly expressed in humanneutrophils. The FLAP gene is located at 13q12 and the gene has beenlinked to increased risk for both myocardial infarction and stroke inseveral populations. A number of polymorphisms and haplotypes in thegene encoding FLAP have been identified in individuals (U.S. PatentApplication 2005113408; Sayers, Clin. Exp. Allergy, 33(8):1103-10, 2003;Kedda, et al., Clin. Exp. Allergy, 35(3):332-8, 2005). Particular FLAPhaplotypes have been linked to myocardial infarction and stroke inseveral populations (Helgadottir A et al Nature Genet 36:233-239 (2004);Helgadottir A et al Am J Hum Genet 76:505-509 (2004); Lohmussaar E et alStroke 36: 731-736 (2005); Kajimoto K et al Circ J 69:1029-1034 (2005).Previously, polymorphisms in certain genes have been demonstrated tocorrelate with responsiveness to given therapies, for example, theresponsiveness of cancers to particular chemotherapeutic agents(Erichsen, et al., Br. J. Cancer, 90(4):747-51, 2004; Sullivan, et al.,Oncogene, 23(19):3328-37, 2004). Therefore, patients who are underconsideration for treatment with the novel FLAP inhibitors describedherein, or drug combinations that include such novel FLAP inhibitors,may be screened for potential responsiveness to treatment based on theirFLAP polymorphisms, or haplotypes.

Additionally, polymorphisms in any of the synthetic or signaling genesdedicated to the leukotriene pathway could result in a patient who ismore responsive or less responsive to leukotriene modulator therapy(either FLAP or 5-LO inhibitor or leukotriene receptor antagonists). Thegenes dedicated to the leukotriene pathway are 5-lipoxygenase,5-lipoxygenase-activating protein, LTA₄ hydrolase, LTC₄ synthase, LTB₄receptor 1 (BLT₁), LTB₄ receptor 2 (BLT₂), cysteinyl leukotrienereceptor 1 (CysLT₁R), cysteinyl leukotriene receptor 2 (CysLT₂R). Forexample, the 5-LO gene has been linked to aspirin intolerant asthma andairway hyperresponsiveness (Choi J H et al Hum Genet 114:337-344 (2004);Kim, S H et al Allergy 60:760-765 (2005). Genetic variants in thepromoter region of 5-LO have been shown to predict clinical responses toa 5LO inhibitor in asthmatics (Drazen et al, Nature Genetics, 22,p168-170, (1999). The LTC₄ synthase gene has been linked to atopy andasthma (Moissidis I et al Genet Med 7:406-410 (2005). The CysLT₂receptor has been linked to asthma and atopy (Thompson M D et alPharmacogenetics 13:641-649 (2003); Pillai S G et al Pharmacogenetics14:627-633 (2004); Park J S et al Pharmacogenet Genomics 15:483-492(2005); Fukai H et al Pharmacogenetics 14:683-690 (2004). Anypolymorphisms in any leukotriene pathway gene or combination ofpolymorphisms or haplotypes may result in altered sensitivity of thepatient to therapy aimed at reducing the pathological effects ofleukotrienes. Selection of patients who might best respond to theleukotriene modulator therapies described herein may include knowledgeof polymorphisms in the leukotriene pathway genes and also knowledge ofthe expression of leukotriene-driven mediators. Patient selection couldbe made on the basis of leukotriene pathway genotype alone, phenotypealone (biomarkers or functional markers) or any combination of genotypeand phenotype.

A “haplotype,” as described herein, refers to a combination of geneticmarkers (“alleles”). A haplotype can comprise one or more alleles (e.g.,a haplotype containing a single SNP), two or more alleles, three or morealleles, four or more alleles, or five or more alleles. The geneticmarkers are particular “alleles” at “polymorphic sites” associated withFLAP. A nucleotide position at which more than one sequence is possiblein a population is referred to herein as a “polymorphic site.” Where apolymorphic site is a single nucleotide in length, the site is referredto as a single nucleotide polymorphism (“SNP”). For example, if at aparticular chromosomal location, one member of a population has anadenine and another member of the population has a thymine at the sameposition, then this position is a polymorphic site, and, morespecifically, the polymorphic site is a SNP. Polymorphic sites can allowfor differences in sequences based on substitutions, insertions ordeletions. Each version of the sequence with respect to the polymorphicsite is referred to herein as an “allele” of the polymorphic site. Thus,in the previous example, the SNP allows for both an adenine allele and athymine allele.

Typically, a reference sequence is referred to for a particularsequence. Alleles that differ from the reference are referred to as“variant” alleles. The term “variant FLAP” as used herein, refers to asequence that differs from a reference FLAP sequence, but is otherwisesubstantially similar. The genetic markers that make up the haplotypesdescribed herein are FLAP variants. In certain embodiments the FLAPvariants are at least about 90% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 91% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 92% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 93% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 94% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 95% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 96% similar to a reference sequence. Inother embodiments the FLAP variants are at least about 97% similar to areference sequence. In other embodiments the FLAP variants are at leastabout 98% similar to a reference sequence. In other embodiments the FLAPvariants are at least about 99% similar to a reference sequence.

Additionally, in certain embodiments the FLAP variants differ from thereference sequence by at least one base, while in other embodiments theFLAP variants differ from the reference sequence by at least two bases.In other embodiments the FLAP variants differ from the referencesequence by at least three bases, and in still other embodiments theFLAP variants differ from the reference sequence by at least four bases.

Additional variants can include changes that affect a polypeptide, e.g.,the FLAP polypeptide. The polypeptide encoded by a reference nucleotidesequence is the “reference” polypeptide with a particular referenceamino acid sequence, and polypeptides encoded by variant alleles arereferred to as “variant” polypeptides with variant amino acid sequences.The FLAP nucleic acid sequence differences, when compared to a referencenucleotide sequence, can include the insertion or deletion of a singlenucleotide, or of more than one nucleotide, resulting in a frame shift;the change of at least one nucleotide, resulting in a change in theencoded amino acid; the change of at least one nucleotide, resulting inthe generation of a premature stop codon; the deletion of severalnucleotides, resulting in a deletion of one or more amino acids encodedby the nucleotides; the insertion of one or several nucleotides, such asby unequal recombination or gene conversion, resulting in aninterruption of the coding sequence; duplication of all or a part of asequence; transposition; or a rearrangement of a nucleotide sequence, asdescribed in detail above. Such sequence changes alter the polypeptideencoded by a FLAP nucleic acid. For example, if the change in thenucleic acid sequence causes a frame shift, the frame shift can resultin a change in the encoded amino acids, and/or can result in thegeneration of a premature stop codon, causing generation of a truncatedpolypeptide.

By way of example, a polymorphism associated with a susceptibility tomyocardial infarction (MI), acute coronary syndrome (ACS), stroke orperipheral arterial occlusive disease (PAOD) can be a synonymous changein one or more nucleotides (i.e., a change that does not result in achange in the amino acid sequence). Such a polymorphism can, forexample, alter splice sites, decrease or increase expression levels,affect the stability or transport of mRNA, or otherwise affect thetranscription or translation of the polypeptide. The haplotypesdescribed below are found more frequently in individuals with MI, ACS,stroke or PAOD than in individuals without MI, ACS, stroke or PAOD.Therefore, these haplotypes may have predictive value for detecting asusceptibility to MI, ACS, stroke or PAOD in an individual.

Several variants of the FLAP gene have been reported to correlate withthe incidence of myocardial infarction in patients (Hakonarson, JAMA,293(18):2245-56, 2005), plus FLAP gene markers reportedly associatedwith the risk for developing asthma have been described in U.S. Pat. No.6,531,279. Methods for identifying FLAP sequence variants are described,e.g., in U.S. Publication No. 2005/0113408, and in U.S. Pat. No.6,531,279, incorporated herein by reference herein in their entirety.

By way of example only, a haplotype associated with a susceptibility tomyocardial infarction or stroke comprises markers SG13S99, SG13S25,SG13S377, SG13S106, SG13S32 and SG13S35 at the 13q12-13 locus. Or, thepresence of the alleles T, G, G, G, A and G at SG13S99, SG13S25,SG13S377, SG13S106, SG13S32 and SG13S35, respectively (the B6haplotype), is diagnostic of susceptibility to myocardial infarction orstroke. Or, a haplotype associated with a susceptibility to myocardialinfarction or stroke comprises markers SG13S99, SG1 3S25, SG13S106,SG13S30 and SG13S42 at the 13q12-13 locus. Or, the presence of thealleles T, G, G, G and A at SG13S99, SG13S25, SG13S106, SG13S30 andSG13S42, respectively (the B5 haplotype), is diagnostic ofsusceptibility to myocardial infarction or stroke Or, a haplotypeassociated with a susceptibility to myocardial infarction or strokecomprises markers SG13S25, SG13S106, SG13S30 and SG13S42 at the 13q12-13locus. Or, the presence of the alleles G, G, G and A at SG13S25,SG13S106, SG13S30 and SG13S42, respectively (the B4 haplotype), isdiagnostic of susceptibility to myocardial infarction or stroke. Or, ahaplotype associated with a susceptibility to myocardial infarction orstroke comprises markers SG13S25, SG13S106, SG13S30 and SG13S32 at the13q 12-13 locus. Or, the presence of the alleles G, G, G and A atSG13S25, SG13S106, SG13S30 and SG13S32, respectively (the Bs4haplotype), is diagnostic of susceptibility to myocardial infarction orstroke. In such embodiments just described, patients who are underconsideration for treatment with compounds of Formula (A), or drugcombinations described herein that include compounds of Formula (A), maybe screened for potential responsiveness to treatment with compounds ofFormula (A) based on such haplotypes.

By way of example only, a haplotype associated with a susceptibility tomyocardial infarction or stroke comprises: markers SG13S99, SG13S25,SG13S114, SG13S89 and SG13S32 at the 13q12-13 locus The presence of thealleles T, G, T, G and A at SG13S99, SG13S25, SG13S114, SG13S89 andSG13S32, respectively (the A5 haplotype), is diagnostic ofsusceptibility to myocardial infarction or stroke; The haplotypeassociated with a susceptibility to myocardial infarction or strokecomprises markers SG13S25, SG13S114, SG13S89 and SG13S32 at the 13q12-13locus The presence of the alleles G, T, G and A at SG13S25, SG13S114,SG13S89 and SG13S32, respectively (the A4 haplotype), is diagnostic ofsusceptibility to myocardial infarction or stroke. In such embodimentsjust described, patients who are under consideration for treatment withcompounds of Formula (A), or drug combinations described herein thatinclude compounds of Formula (A), may be screened for potentialresponsiveness to treatment with compounds of Formula (A) based on suchhaplotypes.

Detecting haplotypes can be accomplished by methods known in the art.These methods are capable of detecting sequences at polymorphic sites,and, therefore, patients may be selected for treatment using genotypeselection of FLAP, 5-LO or other leukotriene pathway gene polymorphisms.The presence or absence of a leukotriene pathway gene polymorphism orhaplotype can be determined by various methods, including, for example,using enzymatic amplification, restriction fragment length polymorphismanalysis, nucleic acid sequencing, electrophoretic analysis of nucleicacid from the individual, or any combination thereof. In certainembodiments, determination of a SNP or haplotype may identify patientswho will respond to, or gain benefit from, treatment with compounds ofFormula (A). By way of example, methods of diagnosing a susceptibilityto myocardial infarction or stroke in an individual, comprisesdetermining the presence or absence of certain single nucleotidepolymorphisms (SNPs) or of certain haplotypes, wherein the presence ofthe SNP or the haplotype is diagnostic of susceptibility to myocardialinfarction or stroke.

Phenotype Analysis: Biomarkers

Patients who are under consideration for treatment with compounds ofFormula (A), or drug combinations described herein that includecompounds of Formula (A), may be screened for potential responsivenessto treatment based on leukotriene-driven inflammatory biomarkerphenotypes.

Patient screening based on leukotriene-driven inflammatory biomarkerphenotypes may be used as an alternative to, or it may be complimentarywith, patient screening by leukotriene pathway gene haplotype detection.The term “biomarker” as used herein refers to a characteristic which canbe measured and evaluated as an indicator of normal biologicalprocesses, pathological processes, or pharmacological responses totherapeutic intervention. Thus a biomarker may be any substance,structure or process which can be measured in the body, or its products,and which may influence or predict the incidence of outcome or disease.Biomarkers may be classified into markers of exposure, effect, andsusceptibility. Biomarkers can be physiologic endpoints, by way ofexample blood pressure, or they can be analytical endpoints, by way ofexample, blood glucose, or cholesterol concentrations. Techniques, usedto monitor and/or measure biomarkers include, but are not limited to,NMR, LC-MS, LC-MS/MS, GC-MS, GC-MS/MS, HPLC-MS, HPLC-MS/MS, FT-MS,FT-MS/MS, ICP-MS, ICP-MS/MS, peptide/protein sequencing, nucleic acidsequencing, electrophoresis techniques, immuno-assays, immuno-blotting,in-situ hybridization, fluorescence in-situ hybridization, PCR,radio-immuno assays, and enzyme-immuno assays. Single nucleotidepolymorphisms (SNPs) have also been useful for the identification ofbiomarkers for propensity to certain diseases and also susceptibility orresponsiveness to drugs such as chemotherapeutic agents and antiviralagents. These techniques, or any combination thereof, may be used toscreen patients for leukotriene-dependent or leukotriene mediateddiseases or conditions, wherein such patients may be beneficiallytreated with compounds of Formula (A), or drug combinations describedherein that include compounds of Formula (A).

By way of example only, patients may be selected for treatment withcompounds of Formula (A), or drug combinations described herein thatinclude compounds of Formula (A), by screening for enhanced inflammatoryblood biomarkers such as, but not limited to, stimulated LTB₄, LTC₄,LTE₄, myeloperoxidase (MPO), eosinophil peroxidase (EPO), C-reactiveprotein (CRP), soluble intracellular adhesion molecule (sICAM), monocytechemoattractant protein (MCP-1), monocyte inflammatory protein (MIP-1α),interleukin-6 (IL-6), the TH2 T cell activators interleukin 4 (IL-4),and 13 (IL-13) and other inflammatory cytokines. In certain embodiments,patients with inflammatory respiratory diseases , including but notlimited to, asthma and COPD, or with cardiovascular diseases, areselected as those most likely to be responsive to leukotriene synthesisinhibition using compounds of Formula (A) by using a panel ofleukotriene driven inflammatory biomarkers.

Phenotype Analysis: Functional Markers

Patients who are under consideration for treatment with compounds ofFormula (A), or drug combinations described herein that includecompounds of Formula (A), may be screened for response to knownmodulators of the leukotriene pathway. Patient screening by evaluationof functional markers as indicators of a patient's response to knownmodulators of the leukotriene pathway may be used as an alternative to,or it may be complimentary with, patient screening by leukotrienepathway gene haplotype detection (genotype analysis) and/ormonitoring/measurement of leukotriene-driven inflammatory biomarkerphenotypes. Functional markers may include, but are not limited to, anyphysical characteristics associated with a leukotriene dependentcondition or disease, or knowledge of current or past drug treatmentregimens.

By way of example only, changes in lung volume and/or function may beused as a functional marker for leukotriene-dependent or leukotrienemediated diseases or conditions, such as respiratory diseases. Lungfunction tests may be used to screen patients, with suchleukotriene-dependent or leukotriene mediated diseases or conditions,for treatment using compounds of Formula (A) or pharmaceuticalcompostitons or medicaments which include compounds of Formula (A). Suchtests include, but are not limited to, evaluation of lung volumes andcapacities, such as tidal volume, inspiratory reserve volume, expiratoryreserve volume, residual volume, inspiratory capacity, functionalresidual capacity, vital capacity, total lung capacity, respiratoryminute volume, alveolar ventilation, timed vital capacity, andventilatory capacity. Method of measurement of lung volumes andcapacities include, but are not limited to, maximum expiratory flowvolume curve, forced expiratory volume in 1 sec. (FEV1), and peakexpiratory flow rate. In addition, other lung function tests used asfunctional markers for patient evaluation described herein include, butare not limited to, respiratory muscle power, maximum inspiratorypressure, maximum expiratory pressure, transdiaphragmatic pressure,distribution of ventilation, single breath nitrogen test, pulmonarynitrogen washout, and gas transfer.

Additionally, the knowledge of a patients past or current treatmentregimen may be used as a functional marker to assist in screeningpatients for treatment of leukotriene dependent conditions or diseasesusing compounds of Formula (A) or pharmaceutical compositions ormedicaments which include compounds of Formula (A). By way of exampleonly, such treatment regimens may include past or current treatmentusing zileuton(Zyflo™), montelukast (Singulair™), pranlukast (Onon™),zafirlukast (Accolate™).

Also, patients who are under consideration for treatment with compoundsof Formula (A), or drug combinations described herein that includecompounds of Formula (A), may be screened for functional markers whichinclude, but are not limited to, reduced eosinophil and/or basophil,and/or neutrophil, and/or monocyte and/or dendritic cell and/orlymphocyte recruitment, decreased mucosal secretion, decreased mucosaledema, and/or increased bronchodilation.

Methods for the identification of a patient in need of treatment forleukotriene-dependent or leukotriene mediated conditions or diseases,and exemplary, non-limiting treatment methods are shown in FIG. 14, FIG.15 and FIG. 16, wherein a patient sample is analyzed and the informationobtained is used to identify possible treatment methods. It is expectedthat one skilled in the art will use this information in conjunctionwith other patient information, including, but not limited to age,weight, sex, diet, and medical condition, to choose a treatment method.It is also expected that each piece of information will be given aparticular weight in the decision process. In certain embodiments, theinformation obtained from the diagnostic methods described above and anyother patient information, including, but not limited to age, weight,sex, diet, and medical condition, are incorporated into an algorithmused to elucidate a treatment method, wherein each piece of informationwill be given a particular weight in the decision process.

In certain embodiments a patient sample is analyzed for leukotriene genehaplotypes, by way of example only, FLAP haplotypes, and the informationobtained identifies a patient in need of treatment using varioustreatment methods. Such treatment methods include, but are not limitedto, administering a therapeutic effective amount of a compound ofFormula (A) or pharmaceutical composition or medicament which includes acompound of Formula (A), administering a therapeutic effective amount ofa compound of Formula (A) or pharmaceutical composition or medicamentwhich includes a compound of Formula (A), in combination with atherapeutic effective amount of a leukotriene receptor antagonist (byway of example , CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a compound of Formula(A) or pharmaceutical composition or medicament which includes acompound of Formula (A), in combination with a therapeutic effectiveamount of another anti-inflammatory agent. In other embodiments apatient sample is analyzed for leukotriene gene haplotypes, by way ofexample only, FLAP haplotypes, and/or phenotype biomarkers, and/orphenotype functional marker responses to leukotriene modifying agents.The patient may then be treated using various treatment methods. Suchtreatment methods include, but are not limited to, administering atherapeutic effective amount of a compound of Formula (A) orpharmaceutical composition or medicament which includes a compound ofFormula (A), administering a therapeutic effective amount of a compoundof Formula (A) or pharmaceutical composition or medicament whichincludes a compound of Formula (A), in combination with a therapeuticeffective amount of a leukotriene receptor antagonist (by way ofexample, CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a compound of Formula(A) or pharmaceutical composition or medicament which includes acompound of Formula (A), in combination with a therapeutic effectiveamount of another anti-inflammatory agent. In still other embodiments apatient sample is analyzed for leukotriene gene haplotypes, by way ofexample only, FLAP haplotypes, and phenotype biomarkers, and phenotypefunctional marker responses to leukotriene modifying agents. The patientmay then be treated using various treatment methods. Such treatmentmethods include, but are not limited to, administering a therapeuticeffective amount of a FLAP inhibitor, or pharmaceutical composition ormedicament which includes a FLAP inhibitor, administering a therapeuticeffective amount of a FLAP inhibitor, or pharmaceutical composition ormedicament which includes a FLAP inhibitor, in combination with atherapeutic effective amount of a leukotriene receptor antagonist (byway of example, CysLT₁/CysLT₂ antagonist or CysLT₁ antagonist), oradministering a therapeutic effective amount of a FLAP inhibitor, orpharmaceutical composition or medicament which includes a FLAPinhibitor, in combination with a therapeutic effective amount of anotheranti-inflammatory agent.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may comprise one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES Example 1(E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylicacid

Step 1: 3-Formyl-5-methoxypyridine

To a solution of 3-Bromo-5-methoxypyridine (2.5 g, 13.3 mmol) inanhydrous diethyl ether cooled to −100° C. was added n-butyllithium(2.5M soln in hexanes: 5.85 mL, 14.6 mmol) dropwise whilst maintainingan internal temperature <−94° C. After subsequent stirring for 30minutes, anhydrous DMF (1.34 mL, 17.3 mmol) was added and the reactionmixture allowed to warm to −60° C.. The solution was then poured intosat'd. aq. NaCl soln. and extracted with diethyl ether (3×100 mL), theethereal phase dried (K₂CO₃), filtered and evaporated in vacuo. Theresidue was purified on silica gel eluting with a gradient of 0 to 30%EtOAc in hexanes to afford the title material as an oil.

Step 2: Ethyl (Z)-2-Azido-3-(5-methoxy-pyridin-3-yl)-acrylate

To a cooled (−15° C.) solution of anhydrous EtOH (270 mL) was addedsodium metal (4.46 g, 0.194 mol) slowly. After complete reaction amixture of 3-formyl-5-methoxypyridine (7.5 g, 54.7 mmol) andethylazidoacetate (25.0 g, 0.194 mol) was added so as to maintain aninternal temperature of −15° C. The reaction mixture was kept at −15° C.for 72 hours after which it was poured into a 30% aq. NH₄Cl solution,extracted with EtOAc (2×250 mL), the organic phase dried (MgSO₄),filtered and evaporated in vacuo. The residue was purified on silica geleluting with a gradient of 0 to 35% EtOAc in hexanes to afford the titlecompound.

Step 3: Ethyl 5-Methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

In a pressure vessel, Ethyl(Z)-2-azido-3-(5-methoxy-pyridin-3-yl)-acrylate (500 mg) was dissolvedin o-xylene (65 mL), sealed and heated at 170° C. for 30 mins. Thevessel was cooled to −20° C. for 24 hours after which the product wasobtained by filtration as colorless crystals. The remaining filtrate wasevaporated to dryness and the residue purified on silica gel elutingwith a gradient of 0 to 2% MeOH in DCM to isolate the remaining productas a yellow solid.

Step 4: of Ethyl1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

To Ethyl 5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylate isolated instep 3 (166 mg; 0.753 mmol) in DMF (2 mL) and THF (1 mL) cooled to 0° C.was added solid sodium hydride (60% dispersion in mineral oil; 40 mg,1.00 mmol) and the solution allowed to warm to ambient temperature.4-chlorobenzylchloride (181 mg, 1.12 mmol) was then added and thereaction maintained at ambient temperature. After completion (asdetermined by TLC analysis) the reaction mixture was partitioned betweenEtOAc and water, the aqueous layer extracted with EtOAc, the combinedorganic phases dried (MgSO₄), filtered and evaporated. The residue waspurified on silica gel eluting with a gradient of 0 to 10% EtOAc inhexanes to afford the title compound as a colorless solid.

Step 5:[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanol

To Ethyl1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylatefrom step 4 (170 mg, 0.493 mmol) in THF (4 mL), was added LiAlH₄ (21 mg,0.542 mmol) and heated to reflux for 30 min. After cooling, the reactionmixture was poured into water, extracted with EtOAc (4×25 mL), theorganic phase dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was purified on silica gel eluting with a gradient of 0 to 40%EtOAc in hexanes to yield the title alcohol.

Step 6:1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde

[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanol(100 mg, 0.330 mmol), isolated previously was dissolved in DCM (5 ml)and cooled to 0° C. Dess-Martin periodinane (168 mg, 0.396 mmol) wasadded and LCMS indicated complete reaction after 30 min. The reactionmixture was diluted with DCM and sat′d aq NaHCO₃ solution added followedby vigorous stirring for 30 min. The organic phase was separated, dried(Na₂SO₄), filtered and evaporated. The residue was taken up in a smallvolume of CHCl₃ and filtered to remove excess iodinane byproducts andevaporated to afford the crude title compound used without furtherpurification.

Step 7: Ethyl(E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylate

To an ice-cooled solution of triethylphosphonoacetate (725 μL, 3.62mmol) in THF (8 mL) was added sodium hydride (60% dispersion in mineraloil; 152 mg, 3.80 mmol) and the mixture allowed to attain ambienttemperature. The solution was then cooled to −78° C. and a solution of1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde(845 mg, 2.81 mmol) in THF (8 mL) was added dropwise via syringe. Thereaction was allowed to warm to ambient temperature after which it waspartitioned between EtOAc and aq NH₄Cl solution, the aqueous layerextracted with EtOAc and the combined organic phases dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was purified on silica geleluting with a gradient of 0 to 100% EtOAc to afford the title ester asa colorless solid.

Step 8:(E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylicacid

To a solution of Ethyl(E)-3-[1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylate(100 mg, 0.270 mmol) isolated previously in THF (0.75 mL), MeOH (0.75mL) and H₂O (0.75 mL) was added LiOH.H₂O (50 mg) and the mixture heatedto 60° C. After completion of the reaction as judged by LCMS analysis,the mixture was diluted with EtOAc and water and solid citric acid addeduntil the aqueous layer attained a pH of ˜4. The organic phase wasseparated, washed with water, dried (MgSO₄), filtered and evaporated toafford the title acid as a yellow solid. LCMS (ESI), M+H 343.

Example 2 2:3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionicacid

To a solution of(E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylicacid (Example 1; 95 mg, 0.277 mmol) in a mixture of EtOH (2 mL) andEtOAc (2 mL) was added Pd/C (˜20 mg) and maintained under an atmosphereof H₂ for 12 hrs. The resulting slurry was filtered through celiteeluting with EtOAc, and the solvent evaporated to afford the title acidas a colorless solid. LCMS (ESI) M+H 345.

Example 33-[1-(4-Chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionicacid

Step 1: Ethyl3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-proprionate

To a solution of Ethyl(E)-3-[1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylate(100 mg, 0.270 mmol) in a mixture of EtOH (2 mL) and EtOAc (2 mL) wasadded Pd/C (˜15 mg) and maintained under an atmosphere of H₂ for 36 hrs.The resulting slurry was filtered through celite eluting with EtOAc, andthe solvent evaporated to afford the title acid as a green oil usedwithout further purification.

Step 2: Ethyl3-[1-(4-Chloro-benzyl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate

To an ice-cooled suspension of anhydrous AlCl₃ (113 mg, 0.847 mmol) inbenzylmercaptan (400 μL, 3.41 mmol) was added Ethyl3-[1-(4-chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-proprionate(100 mg, 0.268 mmol) as a solution in DCM (1.5 mL). After completion ofthe reaction as evidenced by TLC analysis, 1M HCl was added carefully tothe mixture and extracted with DCM. The organic phase was dried(Na₂SO₄), filtered and evaporated in vacuo. The residue was purified onsilica gel eluting with a gradient of 0 to 3% MeOH in DCM to give thetitle phenol.

Step 3: Ethyl3-[1-(4-Chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate

To a solution of the aforementioned Ethyl3-[1-(4-chloro-benzyl)-5-hydroxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate(68 mg, 0.190 mmol) in DMF (1 mL) was added 2-chloromethylquinolinehydrochloride (49 mg, 0.228 mmol), cesium carbonate (124 mg, 0.380 mmol)and catalytic TBAI. The mixture was then heated to 55° C. for 12 hoursafter which it was partitioned between EtOAc and water, the aqueouslayer extracted with EtOAc, the combined organic phases dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was purified on silica geleluting with a gradient of 0 to 30% EtOAc in hexanes to afford the titleester.

Step 4:3-[1-(4-Chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionicacid

Ethyl3-[1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-propionate(90 mg, 0.180 mmol) was dissolved in a mixture of MeOH:THF:H₂O (1:1:1, 2mL) and LiOH.H₂O (25 mg) added. The mixture was heated to 60° C. andmonitored by LCMS. After complete reaction the solution was partitionedbetween EtOAc and water and the aqueous layer acidified with solidcitric acid to pH˜4, the organic layer separated, washed with water,dried (MgSO₄), filtered and evaporated to yield the title acid. LCMS(ESI) M+H 472.

Example 4 3-[5-Chloro-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid

Step 1: 2,2-Dimethyl-pent-4-ynoic acid ethyl ester

Diisopropylamine (45.9 mL, 0.33 mol) was dissolved in THF (300 mL) andcooled to 0° C. under N₂. n-Butyllithium (131.0 mL, 0.33 mol) was addeddropwise over 30 minutes, the mixture was stirred at 0° C. for anadditional 30 minutes, and then cooled to −78° C. Ethyl isobutyrate (40mL, 0.30 mol) was added dropwise in THF (30 mL) and the mixture wasstirred at −78° C. for 1 hour. Propargyl bromide (36.4 mL, 0.33 mol) wasadded dropwise in HMPA (60 mL). The mixture was stirred at −78° C. for 1hour and then quenched with saturated NH₄Cl solution and warmed to roomtemperature. THF was removed in vacuo, and the residue was dissolved inether and washed four times with water. The organic layer was dried overMgSO₄, filtered, and concentrated. The crude material was distilledunder reduced pressure (˜29 inHg, bp 68-70° C.) to obtain the desiredproduct.

Step 2: 6-Chloro-2-iodo-pyridin-3-ylamine

5-Amino-2-chloropyridine (5.0 g, 0.039 mol) was dissolved in EtOH (25mL), and silver sulfate (13.3 g, 0.043 mol) and iodine (10.9 g, 0.043mol) were added. The reaction was stirred at room temperature overnight,and then the mixture was filtered over Celite to remove solids. Thefiltrate was concentrated and purified on silica gel (0-50% EtOAc inhexanes) to give the desired product.

Step 3: 5-(3-Amino-6-chloro-pyridin-2-yl)-2,2-dimethyl-pent-4-ynoic acidethyl ester

PdCl₂ (0.200 g, 1.13 mmol), CuI (0.214 g, 1.13 mmol), and PPh₃ (0.590,2.25 mmol) were suspended in NEt₃ (150 mL) and stirred under N₂.6-Chloro-2-iodo-pyridin-3-ylamine (5.7 g, 2.24 mmol) was added, followedby 2,2-dimethyl-pent-4-ynoic acid ethyl ester (5.2 g, 3.37 mmol), andthe reaction was stirred overnight at room temperature. The reactionmixture was concentrated and purified on silica gel (0-50% EtOAc inhexanes) to give the desired product.

Step 4: of3-(5-Chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acidethyl ester

KOtBu (5.5 g, 0.049 mol) was suspended in DME (50 mL) under N₂.5-(3-Amino-6-chloro-pyridin-2-yl)-2,2-dimethyl-pent-4-ynoic acid ethylester (6.6 g, 0.024 mol) was dissolved in DME (50 mL) and added dropwiseat room temperature. The reaction was stirred for 1 hour until nostarting material was seen by TLC analysis. The reaction was quenchedwith water, and the mixture was extracted with EtOAc three times. Theorganic layer was dried over MgSO₄, filtered, concentrated, and purifiedon silica gel (0-100% EtOAc in hexanes) to give the desired indoleproduct.

Step 5:3-[5-Chloro-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester

3-(5-Chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acidethyl ester (1.0 g, 3.56 mmol), 4-chlorobenzyl chloride (0.86 g, 5.34mmol), Cs₂CO₃ (5.8 g, 17.80 mmol), and tetrabutylammonium iodide (1.3 g,3.57 mmol) were suspended in DMF (˜5 mL) and stirred at 60° C. overnightunder N₂. DMF was removed in vacuo, the residue was dissolved in etherand water, and the aqueous layer was extracted three times with ether.The combined organic layers were washed twice with water, once withbrine, dried over MgSO₄, filtered and concentrated. The crude materialwas purified by silica gel (0-100% EtOAc in hexanes) to obtain thedesired ester.

Step 6:3-[5-Chloro-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propioncacid

3-[5-Chloro-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (0.025 g, 0.062 mmol) was dissolved in THF (0.1 mL),MeOH (0.1 mL), and H₂O (0.1 mL). LiOH (0.01 g, 0.238 mmol) was added andthe reaction was heated to 60° C. for 2 hours. Once no starting materialwas seen by LCMS, the reaction was cooled to room temperature anddiluted with EtOAc and water. The mixture was neutralized with solidcitric acid to ˜pH 5, the aqueous layer was extracted three times withEtOAc, the combined organics were washed twice with water, once withbrine, dried over MgSO₄, filtered and concentrated to give the desiredacid. LCMS (ESI) M+H 379.

Example 5 Synthesis of3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

Step 1: Synthesis of 2-Iodo-6-methoxy-pyridin-3-ylamine

5-Amino-2-methoxypyridine (10.0 g, 0.081 mol) was dissolved in EtOH (50mL), and silver sulfate (27.6 g, 0.089 mol) and iodine (22.5 g, 0.089mol) were added. The reaction was stirred at room temperature overnight,and then the mixture was filtered over Celite to remove solids. Thefiltrate was concentrated and purified on silica gel (0-50% EtOAc inhexanes) to give the desired product.

Step 2: Synthesis of5-(3-Amino-6-methoxy-pyridin-2-yl)-2,2-dimethyl-pent-4-ynoic acid ethylester

PdCl₂ (0.059 g, 0.33 mmol), CuI (0.063 g, 0.33 mmol), and PPh₃ (0.173 g,0.66 mmol) were suspended in NEt₃ (40 mL) and stirred under N₂.2-Iodo-6-methoxy-pyridin-3-ylanine (1.65 g, 6.60 mmol) was added,followed by 2,2-dimethyl-pent-4-ynoic acid ethyl ester (Example 4, Step1; 1.22 g, 7.91 mmol), and the reaction was stirred overnight at roomtemperature. The reaction mixture was concentrated and purified onsilica gel (0-50% EtOAc in hexanes) to give the desired product.

Step 3: Synthesis of3-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acidethyl ester

KOtBu (1.40 g, 12.48 mmol) was suspended in DME (10 mL) under N₂.5-(3-Amino-6-methoxy-pyridin-2-yl)-2,2-dimethyl-pent-4-ynoic acid ethylester (1.64 g, 5.93 mmol) was dissolved in DME (10 mL) and addeddropwise at room temperature. The reaction was stirred for 1 hour untilno starting material was seen by TLC analysis. The reaction was quenchedwith water, and the mixture was extracted with EtOAc three times. Theorganic layer was dried over MgSO₄, filtered, and concentrated, andpurified on silica gel (0-100% EtOAc in hexanes) to give the desiredindole product.

Step 4: Synthesis of3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester

3-(5-Methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-2,2-dimethyl-propionic acidethyl ester (0.350 g, 1.27 mmol), 4-chlorobenzyl chloride (0.306 g, 1.90mmol), Cs₂CO₃ (0.825 g, 2.53 mmol), and tetrabutylammonium iodide (0.094g, 0.25 mmol) were suspended in DMF (˜1 mL) and stirred at 60° C.overnight under N₂. DMF was removed in vacuo, the residue was dissolvedin ether and water, and the aqueous layer was extracted three times withether. The combined organic layers were washed twice with water, oncewith brine, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by silica gel (0-100% EtOAc in hexanes) to obtainthe desired ester.

Step 5: Synthesis of3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

3-[5-Methoxy-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (0.050 g, 0.12 mmol) was dissolved in THF (0.1 mL),MeOH(0.1 mL), and H₂O (0.1 mL). LiOH(0.02 g, 0.50 mmol) was added andthe reaction was heated to 60° C. for 2 hours. Once no starting materialwas seen by LCMS, the reaction was cooled to room temperature anddiluted with EtOAc and water. The mixture was neutralized with solidcitric acid to ˜pH 5, the aqueous layer was extracted three times withEtOAc, the combined organics were washed twice with water, once withbrine, dried over MgSO₄, filtered and concentrated to give the desiredacid. LCMS (ESI) M+H 373.

Example 6 Synthesis of3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

Step 1: Synthesis of3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester

3-[5-Methoxy-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (Example 5, Step 4; 0.133 g, 0.33 mmol) was dissolvedin dichloroethane (5 mL). 3,3-Dimethyl-butyryl chloride (0.12 mL, 0.86mmol) and aluminum chloride (0.137 g, 1.03 mmol) were added, and thereaction was heated to 80° C. under N₂ for 1.5 hours. The reactionmixture was cooled to room temperature and quenched with saturatedpotassium sodium tartrate tetrahydrate solution. The mixture wasextracted with EtOAc three times, the combined organic layers werewashed with water and brine, dried over MgSO₄, filtered, andconcentrated. The crude material was purified on silica gel (0-50% EtOAcin hexanes) to give the desired product.

Step 2: Synthesis of 3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

3-[1-(4-Chloro-benzyl)-3-(3,3-dimethyl-butyryl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (0.020 g, 0.04 mmol) was dissolved in MeCN (1 mL). 1NLiOH (0.16 mL, 0.16 mmol) was added and the reaction was heated to 60°C. overnight. Once no starting material was seen by LCMS, the reactionwas cooled to room temperature and diluted with EtOAc and water. Themixture was neutralized with solid citric acid to ˜pH 5, the aqueouslayer was extracted three times with EtOAc, the combined organics werewashed twice with water, once with brine, dried over MgSO₄, filtered andconcentrated. The crude material was purified by HPLC to give thedesired acid. LCMS (ESI) M+H 471.

Example 7 Synthesis of3-[1-(4-Chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

Step 1: Synthesis of3-[1-(4-Chloro-benzyl)-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester

Aluminum chloride (1.00 g, 7.50 mmol) was suspended in t-butylthiol(0.281 mL, 2.50 mmol), and3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (Example 5, Step 4; 0.200 g, 0.50 mml) was added inCH₂Cl₂ (1 mL). The mixture was stirred at room temperature for 1 hourand then poured onto ice and acidified with 1N HCl. The aqueous mixturewas extracted three times with CH₂Cl₂, and the combined organic layerswere dried over MgSO₄, filtered and concentrated. The crude material waspurified on silica gel (1-10% MeOH in CH₂Cl₂) to give the desired phenolproduct.

Step 2: Synthesis of3-[1-(4-Chloro-benzyl)-5-(Midin-2-ylmethoxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester

3-[1-(4-Chlorobenzyl)-5-hydroxy-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (0.100 g, 0.26 mmol) was dissolved in acetone (2 mL),and 2-chloromethyl-pyridine (0.064 g, 0.39 mmol), tetrabutylammoniumiodide (0.095 g, 0.26 mmol) and K₂CO₃ (0.107 g, 0.77 mol) were added.The mixture was stirred at 65° C. overnight, and two products wereobserved by TLC analysis. The reaction was cooled to room temperature,diluted with water, and extracted with EtOAc three times. The combinedorganic layers were washed with water, brine, dried over MgSO₄,filtered, and concentrated to give a 1:2 mixture of the O-alkylated andN-alkylated products. The crude material was purified by preparative TLCto obtain the O-alkylated title compound.

Step 3: Synthesis of3-[1-(4-Chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

3-[1-(4-Chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionicacid ethyl ester (0.024 g, 0.05 mmol) was dissolved in THF (0.1 mL),MeOH (0.1 mL), and H₂O (0.1 mL). LiOH (0.008 g, 0.20 mmol) was added andthe reaction was heated to 60° C. for 2 hours. Once no starting materialwas seen by LCMS, the reaction was cooled to room temperature anddiluted with EtOAc and water. The mixture was neutralized with solidcitric acid to ˜pH 5, the aqueous layer was extracted three times withEtOAc, the combined organics were washed twice with water, once withbrine, dried over MgSO₄, filtered and concentrated to give the desiredacid. LCMS (ESI) M+H 450.

The following are non limiting examples of the the following Formula(any of which can be used in the methods and compositions describedherein):

3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(pyrazin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionic acid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionic acid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(5-ethyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(6-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(thiazol-4-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionic acid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(2-methyl-thiazol-4-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(benzothiazol-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-quinolin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-quinolin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((S)-1-acetyl-pyrrolidin-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-((R)-1-acetyl-pyrrolidin-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(-((S)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(-((R)-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(2-(4-fluoro-phenyl)-2-hydroxy-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; 3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; and3-[3-tert-Butylsulfanyl-1-(4-chloro-benzyl)-5-(5-methyl-isoxazol-3-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid.

The following are non limiting examples of the the following Formula(any of which can be used in the methods and compositions describedherein):

3-[3-tert-Butylsulfanyl-1-benzyl-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-fluoro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-pyridin-2-yl-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-pyridin-3-yl-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-pyridin-4-yl-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-methoxy-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methyl-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-methyl-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-fluoro-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridazin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionic acid;3-[3-tert-Butylsulfanyl-1-[4-(6-methyl-pyridazin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-thiazol-2-yl-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-thiazol-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-methyl-thiazol-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-methoxy-thiazol-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(2-methoxy-thiazol-4-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-cyano-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4′-cyano-biphenyl-4-ylmethyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(3,5-dimethyl-isoxazol-4-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-[1,3,4]oxadiazol-2-yl-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-methoxy-phenyl)-pyridin-2-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-trifluoromethyl-phenyl)-pyridin-2-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-trifluoromethoxy-phenyl)-pyridin-2-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-methoxy-phenyl)-pyridin-3-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[5-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(3-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(3-fluoro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(3-cyano-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[3-(6-methoxy-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[3-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[3-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; 3-[3-tert-Butylsulfanyl-1-[3-(5-fluoro-pyridin-2-yl)-benzyl]-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(quinolin-2-ylmethyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(6-fluoro-quinolin-2-ylmethyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; and3-[3-tert-Butylsulfanyl-1-(2-methoxy-quinolin-6-ylmethyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid

The following are non limiting examples of the the following Formula(any of which can be used in the methods and compositions describedherein):

3-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propianicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-pyridin-2-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-pyridin-2-yl)-benzyl]-5-(6-fluoro-quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1H-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-pyridin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-(4-cyano-benzyl)-5-(1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(6-trifluoromethyl-pyridin-3-yl)-benzyl]-5-(1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-tert-Butylsulfanyl-1-[4-(5-trifluoromethyl-pyridin-2-yl)-benzyl]-5-(1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; and3-[3-tert-Butylsulfanyl-1-[4-(5-fluoro-pyridin-2-yl)-benzyl]-5-(1-pyridin-2-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid.

The following are non limiting examples of the the following Formula(any of which can be used in the methods and compositions describedherein):

3-[3-Phenylsulfanyl-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-(2,2-Dimethyl-propionyl)-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-Cyclobutanecarbonyl-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; 3-[3-(l-Hydroxy-2,2-dimethyl-propyl)-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-(Cyclobutyl-hydroxy-methyl)-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid;3-[3-(2,2-Dimethyl-propyl)-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid; and3-[3-Cyclobutylmethyl-1-(4-chloro-benzyl)-5-(quinolin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2,2-dimethyl-propionicacid.

The following examples provide illustrative methods for testing theeffectiveness and safety of the compounds of Formula (A), and forforming pharmaceutical compositions of compounds of Formula (A). Forconvenience, the examples use a single formula, such as “Formula (A).”However, the examples apply equally well to all formulas presentedherein that fall within the scope of Formula (A). Thus, the examplesdescribed herein can be applied to compounds having the structure ofFormula (B), Formula (C), Formula (D), Formula (E), Formula (F), Formula(G), Formula (I), Formula (II), Formula (III), Formula (IV), Formula(V), Formula (VI), Formula (VII) Formula (VIII), Formula (IX), Formula(X), Formula (XI), Formula (XII), Formula (XIII), Formula.(XIV), Formula(XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX),Formula (XX), Formula (XXI), Formula (XXII), Formula (XXIII) and Formula(XXIV), as well as to all of the specific compounds that fall within thescope of these generic formulae. These examples are provided forillustrative purposes only and not to limit the scope of the claimsprovided herein.

Example 8 FLAP Binding Assays

A non-limiting example of such a FLAP binding assay is as follows:

Packed human polymorphonuclear cell pellets (1.8×109 cells) (BiologicalSpeciality Corporation) were resuspended, lysed and 100,000 g membranesprepared as described (Charleson et al Mol. Pharmacol, 41, 873-879,1992). 100,000×g pelleted membranes were resuspended in Tris-Tween assaybuffer (100 nM Tris HCl pH 7.4, 140 mM NaCl, 2 mM EDTA, 0.5 mM DTT, 5%glycerol, 0.05% Tween 20) to yield a protein concentration of 50-100ug/mL. 10 uL membrane suspension was added to 96 well Millipore plate,78 μL Tris-Tween buffer, 10 μL ³H MK886 or ³H3-[5-(pyrid-2-ylmethoxy)-3-tert-butylthio-1-benzyl-indol-2-yl]-2,2-dimethylpropionicacid (or ¹²⁵I MK591 derivative Eggler et al, J. Labelled Compounds andRadiopharmaceuticals, 1994, vXXXIV, 1147)) to ˜30,000 cpm, 2 μLinhibitor and incubated for 30 minutes at room temperature. 100 μLice-cold washed buffer was added to the incubation mixture. Plates werethen filtered and washed 3× with 200 μL ice cold Tris-Tween buffer,scintillation bottoms sealed, 100 μL scintillant added, shaken for 15minutes then counted in a TopCount. Specific binding was determined asdefined as total radioactive binding minus non-specific binding in thepresence of 10 μM MK886. IC50s were determined using Graphpad prismanalysis of drug titration curves.

Example 9 Human Blood LTB₄ Inhibition Assay

A non-limiting example of such a human blood LTB₄ inhibition assay is asfollows:

Blood was drawn from consenting human volunteers into heparinized tubesand 125 μl aliquots added to wells containing 2.5 μl 50% DMSO (vehicle)or 2.5 μL drug in 50% DMSO. Samples were incubated for 15 minutes at 37°C. 2 μl calcium ionophore A23817 (from a 50 mM DMSO stock diluted justprior to the assay in Hanks balanced salt solution (Invitrogen)) to 1.25mM) was added, solutions mixed and incubated for 30 minutes at 37° C.Samples were centrifuged at 1,000 rpm (˜200×g) for 10 minutes at 4° C.,plasma removed and a 1:100 dilution assayed for LTB₄ concentration usingELISA (Assay Designs). Drug concentrations to achieve 50% inhibition(IC50's) of vehicle LTB₄ were determined by nonlinear regression(Graphpad Prism) of % inhibition versus log drug concentration.

Example 10 Rat Peritoneal Inflammation and Edema Assay

A non-limiting example of such a rat peritoneal inflammation and edemaassay is as follows:

The in vivo efficacy of leukotriene biosynthesis inhibitors was assessedusing a rat model of peritoneal inflammation. Male Sprague-Dawley rats(weighing 200-300 grams) received a single intraperitoneal (i.p.)injection of 3 ml saline containing zymosan (5 mg/ml) followedimmediately by an intravenous (i.v.) injection of Evans blue dye (2 mlof 1.5% solution). Compounds were administered orally (3 ml/kg in 0.5%methylcellulose vehicle) 2 to 4 hours prior to zymosan injection. One totwo hours after zymosan injection, rats were euthanized, and theperitoneal cavity was flushed with 10 ml phosphate buffered salinesolution (PBS). The resulting fluid was centrifuged at 1,200 rpm for 10minutes. Vascular edema was assesses by quantifying the amount of Evansblue dye in the supernatant using a spectrophotometer (Absorbance 610nm). LTB₄ and cysteinyl leukotriene concentrations in the supernatantwere determined by ELISA. Drug concentrations to achieve 50% inhibitionof plasma leakage (Evans blue dye) and inhibition of peritoneal LTB₄ andcysteinyl leukotrienes could be calculated by nonlinear regression(Graphpad Prism) of % inhibition versus log drug concentration.,

Example 11 Human Leukocyte Inhibition Assay

A non-limiting example of a human leukocyte inhibition assay is asfollows:

Blood was drawn from consenting human volunteers into heparanized tubesand 3% dextran, 0.9% saline equal volume added. After sedimentation ofred blood cells a hypotonic lysis of remaining red blood cells wasperformed and leukocytes sedimented at 1000 rpm. The pellet wasresuspended at 1.25×10⁵ cells/ml and aliquoted into wells containing 2.5μl 20% DMSO (vehicle) or 2.5 μl drug in 20% DMSO. Samples were incubatedfor 5 minutes at 37° C. and 2 μl calcium ionophore A23817 (from a 50 mMDMSO stock diluted just prior to the assay in Hanks balanced saltsolution (Invitrogen)) to 1.25 mM) was added, solutions mixed andincubated for 30 minutes at 37° C. Samples were centrifuged at 1,000 rpm(˜200×g) for 10 minutes at 4° C., plasma removed and a 1:4 dilutionassayed for LTB₄ concentration using ELISA (Assay Designs). Drugconcentrations to achieve 50% inhibition (IC50's) of vehicle LTB₄ weredetermined by nonlinear regression (Graphpad Prism) of % inhibitionversus log drug concentration. Compounds of Formula (A) that weresynthesized in the examples had assays of 1 nM to 10 μM with this assay.

Example 12 Rat Bronchoalveolar Lavage Procedure

A non-limiting example of a rat bronchoalveolar lavage assay is asfollows:

A rat ionophore lung lavage model was utilized to determine efficacy ofleukotriene biosynthesis inhibitors in the target tissue for respiratorytherapy. Male Sprague-Dawley rats (weighing 200-300 grams) wereadministered compound orally (3 ml/kg in 0.5% methylcellulose vehicle) 2to 24 hours prior to lung lavage. At the appropriate time after compoundadministration rats were placed into an enclosed Plexiglas chamber andexposed to CO₂ for a period of 1-2 minutes or until breathing ceased.They were then removed and blood was taken via a cardiac puncture.Cervical dislocation was performed to ensure rats would not recover fromthe CO₂. Subjects were next placed in a supine position, the trachea wasexposed by blunt dissection and a 7 ml bolus of ice cold phosphatebuffered saline solution (PBS with 7% DMSO) containing 20 μg/ml A23187was instilled using a 10 ml syringe equipped with a 20 gauge bluntneedle tip. After a 3-minute period the fluid was withdrawn, mixed withequal parts ice cold methanol and centrifuged at 10,000×g for 10 minutesat 4° C. LTB₄ and cysteinyl leukotriene concentrations in thesupernatant were determined by EIA. Drug concentrations to achieve 50%inhibition of lung LTB₄ and cysteinyl leukotrienes could be calculatedby nonlinear regression (Graphpad Prism) of % inhibition versus log drugconcentration.

Example 13 Pharmaceutical Compositions Example 13a ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (A) is dissolved in DMSO and then mixed with 10 mLof 0.9% sterile saline. The mixture is incorporated into a dosage unitform suitable for administration by injection.

Example 13b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (A) is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 13c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (A), with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 13d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (A) is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 13e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (A) is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Example 13f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (A) is mixed with 1.75 g of hydroxypropyl celluose,10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL ofpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example 13g Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of acompound of Formula (A) is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filterd using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

1. A compound having the structure of Formula (A):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)₂, C(O), -(substituted or unsubstituted C₁-C₆ alkyl), or-(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G, wherein,X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O), —C(O)NH,—NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—, —NR₈S(═O)₂,—OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—, —ON═CH—,—NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—,—C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle; L₄ is a bond,optionally substituted or unsubstituted alkyl, optionally substituted orunsubstituted cycloalkyl, optionally substituted or unsubstitutedalkenyl, optionally substituted or unsubstituted alkynyl; G is H, —CO₂H,tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₉, —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl),-L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted orunsubstituted heteroaryl), or -L₅-(substituted or unsubstituted aryl),wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G isW-G₁, where W is a substituted or unsubstituted aryl, substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₉, —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof.
 2. The compound of claim 1,wherein the compound of Formula (A) is

wherein,

is a N-containing heterocycle selected from the group consisting of amonocyclic heterocycloalkyl, a monocyclic heteroaryl, a bicyclicheterocycloalkyl, a bicyclic heteroaryl, a multicyclic heterocycloalkyl,or a multicyclic heteroaryl; and each R_(a) is independently H, halogen,—N₃, —CF₃, —CN, —NO₂, OH, NH₂, -L_(a)-(substituted or unsubstitutedalkyl), -L_(a)-(substituted or unsubstituted alkenyl),-L_(a)-(substituted or unsubstituted heteroaryl), or -L_(a)-(substitutedor unsubstituted aryl), wherein L_(a) is a bond, O, S, —S(═O), —S(═O)₂,NH, C(O), CH₂, —NHC(O)O, —NHC(O), or —C(O)NH, and n is 0, 1, 2, 3, 4, 5,or 6; or two R_(a) groups on the same ring atom can together form anoxo.
 3. The compound of claim 2, wherein the compound is selected fromthe group consisting of.


4. The compound of claim 2, wherein the compound is

wherein, R₆ is H, L₂-(substituted or unsubstituted alkyl),L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted orunsubstituted alkenyl), L₂-(substituted or unsubstituted cycloalkenyl),L₂-(substituted or unsubstituted heterocycle), L₂-(substituted orunsubstituted heteroaryl), or L₂-(substituted or unsubstituted aryl),where L₂ is a bond, O, S, —S(═O), —S(═O)_(2,), C(O), -(substituted orunsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted C₂-C₆alkenyl); G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted orunsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O,or —OC(O); or G is W-G₁, where W is a substituted or unsubstituted aryl,substituted or unsubstituted heterocycle or substituted or unsubstitutedheteroaryl and G, is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂;

is a N-containing heterocycle selected from the group consisting of amonocyclic heterocycloalkyl, a monocyclic heteroaryl, a bicyclicheterocycloalkyl, a bicyclic heteroaryl, a multicyclic heterocycloalkyl,or a multicyclic heteroaryl; and each R_(a) is independently H, halogen,—N₃, —CF₃, —CN, —NO₂, OH, NH2, -L_(a)-(substituted or unsubstitutedalkyl), -L_(a)-(substituted or unsubstituted alkenyl),-L_(a)-(substituted or unsubstituted heteroaryl), or -L_(a)-(substitutedor unsubstituted aryl), wherein L_(a) is a bond, O, S, —S(═O), —S(═O)₂,NH, C(O), CH₂, —NHC(O)O, —NHC(O), or —C(O)NH, and n is 0, 1, 2, 3, 4, 5,or 6; or two R_(a) groups on the same ring atom can together form anoxo.
 5. The compound of claim 4, wherein R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted alkenyl),where L₂ is a bond, O, S, —S(═O), —S(O)₂, —C(O), or substituted orunsubstituted alkyl.
 6. A compound having the structure of Formula (B):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)_(2,), C(O), -(substituted or unsubstituted C₁-C₆ alkyl),or —(substituted or unsubstituted C₂-C6 alkenyl); R₇ is L₃-X-L₄-G,wherein, X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),—C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,—NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR,C(O)O—, —CH═NO—,—ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,—NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle; L₄is a bond, optionally substituted or unsubstituted alkyl, optionallysubstituted or unsubstituted cycloalkyl, optionally substituted orunsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted orunsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O,or —OC(O); or G is W-G₁, where W is a substituted or unsubstituted aryl,substituted or unsubstituted heterocycle or substituted or unsubstitutedheteroaryl and G₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂-NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₈, —S(═O)₂NH₂—C(O)R₉, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof.
 7. The compound of claim 6,wherein the compound of Formula (B) is

wherein,

is a N-containing heterocycle selected from the group consisting of amonocyclic heterocycloalkyl, a monocyclic heteroaryl, a bicyclicheterocycloalkyl, a bicyclic heteroaryl, a multicyclic heterocycloalkyl,or a multicyclic heteroaryl; and each R_(a) is independently H, halogen,—N₃, —CF₃, —CN, —NO₂, OH, NH₂, -L_(a)-(substituted or unsubstitutedalkyl), -L_(a)-(substituted or unsubstituted alkenyl),-L_(a)-(substituted or unsubstituted heteroaryl), or -L_(a)-(substitutedor unsubstituted aryl), wherein L_(a) is a bond, O, S, —S(═O), —S(═O)₂,NH, C(O), CH₂, —NHC(O)O, —NHC(O), or —C(O)NH, and n is 0, 1, 2, 3, 4, 5,or 6; or two R_(a) groups on the same ring atom can together form anoxo.
 8. The compound of claim 6, wherein the compound is selected fromthe group consisting of.


9. The compound of claim 2, wherein the compound claimed is

wherein, R₆ is H, L₂-(substituted or unsubstituted alkyl),L₂-(substituted or unsubstituted cycloalkyl), L₂-(substituted orunsubstituted alkenyl), L₂-(substituted or unsubstituted cycloalkenyl),L₂-(substituted or unsubstituted heterocycle), L₂-(substituted orunsubstituted heteroaryl), or L₂-(substituted or unsubstituted aryl),where L₂ is a bond, O, S, —S(═O), —S(═O)₂, C(O), —(substituted orunsubstituted C₁-C₆ alkyl), or -(substituted or unsubstituted C₂-C₆alkenyl); G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted orunsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O,or —OC(O); or G is W-G₁, where W is a substituted or unsubstituted aryl,substituted or unsubstituted heterocycle or substituted or unsubstitutedheteroaryl and G, is H, —CO2H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂;

is a N-containing heterocycle selected from the group consisting of amonocyclic heterocycloalkyl, a monocyclic heteroaryl, a bicyclicheterocycloalkyl, a bicyclic heteroaryl, a multicyclic heterocycloalkyl,or a multicyclic heteroaryl; and each R_(a) is independently H, halogen,—N₃, —CF₃, —CN, —NO₂, OH, NH₂, -L_(a)-(substituted or unsubstitutedalkyl), -L_(a)-(substituted or unsubstituted alkenyl),-L_(a)-(substituted or unsubstituted heteroaryl), or -L_(a)-(substitutedor unsubstituted aryl), wherein L_(a) is a bond, O, S, —S(═O), —S(═O)₂,NH, C(O), CH₂, —NHC(O)O, —NHC(O), or —C(O)NH, and n is 0, 1, 2, 3, 4, 5,or 6; or two R_(a) groups on the same ring atom can together form anoxo.
 10. The compound of claim 9, wherein R₆ is L₂-(substituted orunsubstituted alkyl), or L₂-(substituted or unsubstituted alkenyl),where L₂ is a bond, O, S, —S(═O), —S(O)₂, —C(O), or substituted orunsubstituted alkyl.
 11. A pharmaceutical composition for treating aleukotriene-dependent condition or disease in a patient comprising aninhibitor of 5-lipoxygenase activating protein (FLAP) having thestructure of Formula (A):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)_(2,), C(O), -(substituted or unsubstituted C₁-C₆ alkyl),or —(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G,wherein, X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),—C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,—NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—,—ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,—NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle; L₄is a bond, optionally substituted or unsubstituted alkyl, optionallysubstituted or unsubstituted cycloalkyl, optionally substituted orunsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted orunsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O,or —OC(O); or G is W-G₁, where W is a substituted or unsubstituted aryl,substituted or unsubstituted heterocycle or substituted or unsubstitutedheteroaryl and G₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₈, —S(═O)₂NH₂-C(O)R₈, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof; and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition for treating aleukotriene-dependent condition or disease in a patient comprising aninhibitor of 5-lipoxygenase activating protein (FLAP) having thestructure of Formula (B):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)₂, C(O), -(substituted or unsubstituted C₁-C₆ alkyl), or—(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G, wherein,X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O), —C(O)NH,—NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—, —NR₈S(═O)₂,—OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—, —ON═CH—,—NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—,—C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle; L₄ is a bond,optionally substituted or unsubstituted alkyl, optionally substituted orunsubstituted cycloalkyl, optionally substituted or unsubstitutedalkenyl, optionally substituted or unsubstituted alkynyl; G is H, —CO₂H,tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl),-L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted orunsubstituted heteroaryl), or -L₅-(substituted or unsubstituted aryl),wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G isW-G₁, where W is a substituted or unsubstituted aryl, substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₈, —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof; and a pharmaceuticallyacceptable carrier.
 13. A method for treating a leukotriene-dependentcondition or disease in a patient comprising administering to thepatient a therapeutically effective amount of an inhibitor of5-lipoxygenase activating protein (FLAP) having the structure of Formula(A):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)_(2,), C(O), -(substituted or unsubstituted C₁-C₆ alkyl),or —(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G,wherein, X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O),—C(O)NH, —NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—,—NR₈S(═O)₂, —OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—,—ON═CH—, —NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—,—NR₉C(═NR₁₀)—, —C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycle; L₄is a bond, optionally substituted or unsubstituted alkyl, optionallysubstituted or unsubstituted cycloalkyl, optionally substituted orunsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;G is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₈)₂, —NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈,—C(O)R₈, —CON(R₉)₂, —SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted orunsubstituted alkyl), -L₅-(substituted or unsubstituted alkenyl),-L₅-(substituted or unsubstituted heteroaryl), or -L₅-(substituted orunsubstituted aryl), wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O,or —OC(O); or G is W-G₁, where W is a substituted or unsubstituted aryl,substituted or unsubstituted heterocycle or substituted or unsubstitutedheteroaryl and G₁ is H, —CO₂H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH,—OR₈, —C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO2R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₈, —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof.
 14. A method for treating aleukotriene-dependent condition or disease in a patient comprisingadministering to the patient a therapeutically effective amount of aninhibitor of 5-lipoxygenase activating protein (FLAP) having thestructure of Formula (B):

wherein, Y is substituted or unsubstituted heterocycle, substituted orunsubstituted heteroaryl, substituted or unsubstituted aryl or—C(═NR₃)N(R₄)₂, —NR₄C(═NR₃)N(R₄)₂, —NR₄C(═CR₃)N(R₄)₂; where R₃ isindependently selected from H, —S(═O)₂R₄, —S(═O)₂NH₂—C(O)R₄, —CN, —NO₂,heteroaryl, or heteroalkyl; each R₄ is independently selected from H,substituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; or two R₄ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; and or R₃ and R₄ groups can together forma 5-, 6-, 7-, or 8-membered heterocyclic ring; R₆ is H, L₂-(substitutedor unsubstituted alkyl), L₂-(substituted or unsubstituted cycloalkyl),L₂-(substituted or unsubstituted alkenyl), L₂-(substituted orunsubstituted cycloalkenyl), L₂-(substituted or unsubstitutedheterocycle), L₂-(substituted or unsubstituted heteroaryl), orL₂-(substituted or unsubstituted aryl), where L₂ is a bond, O, S,—S(═O), —S(═O)₂, C(O), -(substituted or unsubstituted C₁-C₆ alkyl), or—(substituted or unsubstituted C₂-C₆ alkenyl); R₇ is L₃-X-L₄-G, wherein,X is a bond, O, —C(═O), S, —S(═O), —S(═O)₂, —NH, —NR₈, —NHC(O), —C(O)NH,—NR₈C(O), —C(O)NR₈, —S(═O)₂NH, —NHS(═O)₂, —S(═O)₂NR₈—, —NR₈S(═O)₂,—OC(O)NH—, —NHC(O)O—, —OC(O)NR₈—, —NR₈C(O)O—, —CH═NO—, —ON═CH—,—NR₉C(O)NR₉—, heteroaryl, aryl, —NR₉C(═NR₁₀)NR₉—, —NR₉C(═NR₁₀)—,—C(═NR₁₀)NR₉—, —OC(═NR₁₀)—, or —C(═NR₁₀)O—; L₃ is a bond, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycle; L₄ is a bond,optionally substituted or unsubstituted alkyl, optionally substituted orunsubstituted cycloalkyl, optionally substituted or unsubstitutedalkenyl, optionally substituted or unsubstituted alkynyl; G is H, —CO₂H,tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈, —C(═O)CF₃,—C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂, —C(═NR₁₀)N(R₈)₂,—NR₉C(═NR₁₀)N(R₉)₂, —NR₉C(═CR₁₀)N(R₉)₂, —CO₂R₈, —C(O)R₈, —CON(R₉)₂,—SR₈, —S(═O)R₈, —S(═O)₂R₈, -L₅-(substituted or unsubstituted alkyl),-L₅-(substituted or unsubstituted alkenyl), -L₅-(substituted orunsubstituted heteroaryl), or -L₅-(substituted or unsubstituted aryl),wherein L₅ is —NHC(O)O, —NHC(O), —C(O)NH, —C(O)O, or —OC(O); or G isW-G₁, where W is a substituted or unsubstituted aryl, substituted orunsubstituted heterocycle or substituted or unsubstituted heteroaryl andG₁ is H, —CO2H, tetrazolyl, —NHS(═O)₂R₈, S(═O)₂N(R₉), OH, —OR₈,—C(═O)CF₃, —C(O)NHS(═O)₂R₈, —S(═O)₂NHC(O)R₈, CN, N(R₉)₂,—C(═NR₁₀)N(R₉)₂—NR₉C(═NR₁₀)N(R₉)₂, —NR₉c(═CR₁₀)N(R₉)₂, —CO₂R₈, —CONH₂,—CONHR₈, or —CON(R₈)₂; each R₈ is independently selected fromsubstituted or unsubstituted lower alkyl, substituted or unsubstitutedlower cycloalkyl; each R₉ is independently selected from H, substitutedor unsubstituted lower alkyl, substituted or unsubstituted lowercycloalkyl or two R₉ groups can together form a 5-, 6-, 7-, or8-membered heterocyclic ring; or R₈ and R₉ can together form a 5-, 6-,7-, or 8-membered heterocyclic ring and each R₁₀ is independentlyselected from H, —S(═O)₂R₈, —S(═O)₂NH₂—C(O)R₈, —CN, —NO₂, heteroaryl, orheteroalkyl; R₁₁ is L₇-G, L₇-(substituted or unsubstitutedcycloalkyl)-G, L₇-(substituted or unsubstituted cycloalkenyl)-G,L₇-(substituted or unsubstituted heteroaryl)-G, or L₇-(substituted orunsubstituted aryl)-G, L₇-(substituted or unsubstituted heterocycle)-G,where L₇ is a bond, —C(O), —C(O)NH, (substituted or unsubstituted C₁-C₆alkyl), or (substituted or unsubstituted C₂-C₆ alkenyl); or activemetabolite, or solvate, or pharmaceutically acceptable salt, or apharmaceutically acceptable prodrug thereof.
 15. The method of claim 13,wherein the leukotriene-dependent condition is a respiratory condition.16. The method of claim 15, wherein the respiratory condition is asthma.17. The method of claim 13, wherein the leukotriene-dependent conditionis a cardiovascular condition.
 18. The method of claim 14, wherein theleukotriene-dependent condition is a respiratory condition.
 19. Themethod of claim 18, wherein the respiratory condition is asthma.
 20. Themethod of claim 14, wherein the leukotriene-dependent condition is acardiovascular condition.